Phenyl amino piperidine mTORC inhibitors and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful formodulating mTORC1 activity. The invention also provides pharmaceuticallyacceptable compositions comprising provided compounds of the presentinvention and methods of using such compositions in the treatment ofvarious disorders.

BACKGROUND OF THE INVENTION

The mechanistic target of rapamycin (mTOR) signaling pathway integratesboth intracellular and extracellular signals and serves as a centralregulator of cell metabolism, growth, proliferation and survival.Discoveries that have been made over the last decade show that the mTORpathway is activated during various cellular processes (e.g. tumorformation and angiogenesis, insulin resistance, adipogenesis andT-lymphocyte activation) and is deregulated in human diseases such ascancer and type 2 diabetes. These observations have attracted broadscientific and clinical interest in mTOR. This is highlighted by thegrowing use of mTOR inhibitors [rapamycin and its analogues(rapalogues)] in pathological settings, including the treatment of solidtumors, organ transplantation, coronary restenosis and rheumatoidarthritis.

In particular, mTOR complex 1 (mTORC1) positively regulates cell growthand proliferation by promoting many anabolic processes, includingbiosynthesis of proteins, lipids and organelles, and by limitingcatabolic processes such as autophagy. Much of the knowledge aboutmTORC1 function comes from the use of the bacterial macrolide rapamycin.Upon entering the cell, rapamycin binds to FK506-binding protein of 12kDa (FKBP12) and interacts with the FKBP12-rapamycin binding domain(FRB) of mTOR, thus inhibiting mTORC1 functions (reviewed by Guertin andSabatini, 2007). In contrast to its effect on mTORC1, FKBP12-rapamycincannot physically interact with or acutely inhibit mTOR complex 2(mTORC2)(Jacinto et al., 2004; Sarbassov et al., 2004). On the basis ofthese observations, mTORC1 and mTORC2 have been respectivelycharacterized as the rapamycin-sensitive and rapamycin-insensitivecomplexes. However, this paradigm might not be entirely accurate, aschronic rapamycin treatment can, in some cases, inhibit mTORC2 activityby blocking its assembly (Sarbassov et al., 2006). In addition, recentreports suggest that important mTORC1 functions are resistant toinhibition by rapamycin (Choo et al., 2008; Feldman et al., 2009;Garcia-Martinez et al., 2009; Thoreen et al., 2009). Therefore,selective inhibition of mTORC1 would enable the treatment of diseasesthat involve dysregulation of protein synthesis and cellular metabolism.Furthermore, this detailed understanding of regulating mTORC activationpathways will permit the discovery of new strategies for regulatingabnormal disease processes by modulating mTORC1 activity across itsspectrum of function.

Many diseases are associated with abnormal cellular responses triggeredby events as described above. These diseases include, but are notlimited to, autoimmune diseases, inflammatory diseases, bone diseases,metabolic diseases, neurological and neurodegenerative diseases, cancer,cardiovascular diseases, allergies and asthma, Alzheimer's disease, andhormone-related diseases.

The mechanistic target of rapamycin complex 1 (mTORC1) is a mastergrowth regulator that senses diverse environmental cues, such as growthfactors, cellular stresses, and nutrient and energy levels. Whenactivated, mTORC1 phosphorylates substrates that potentiate anabolicprocesses, such as mRNA translation and lipid synthesis, and limitscatabolic ones, such as autophagy. mTORC1 dysregulation occurs in abroad spectrum of diseases, including diabetes, epilepsy,neurodegeneration, immune response, suppressed skeletal muscle growth,and cancer among others (Howell et al., (2013) Biochemical Societytransactions 41, 906-912; Kim et al., (2013) Molecules and cells 35,463-473; Laplante and Sabatini, (2012) Cell 149, 274-293). Accordingly,there remains a need to find protein kinase inhibitors useful astherapeutic agents.

Additionally, Glucose Transporters (GLUT) are a family of membraneproteins (GLUT1, 2, 3, 4, and 5) that facilitate the transport ofglucose and other hexoses across cell membranes. The transport ofglucose into cells is one of the most important cellular transportevents because of the role in maintaining normal cellular respirationand metabolism (Gould and Holman, (1993) Biochem J., 295, 329-341).Dysfunction or dysregulation of glucose transporters may contribute to,or directly result in, disease states because of the central role thetransporters play in cellular homeostasis and metabolism. For example,mutations in the GLUT1 gene are responsible for the rare autosomaldisorder De Vivo disease, which is characterized by impaired glucosetransport into the brain. Relatedly, elevated levels of GLUT1 inneutrophils has been found to contribute to the inflammatory response incystic fibrosis (CF) patients (Laval et al., (2013) J. Immunol, 190(12),6043-50). GLUT inhibition may normalize cellular metabolism and responsein affected cells, including immune cells such as neutrophils.Therefore, GLUT inhibition would enable the treatment of cysticfibrosis, as well as autoimmune diseases characterized by abnormal GLUTexpression or activity.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors mTORC1 inhibitors. Such compounds have the general Formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with mTORC1. Such diseases,disorders, or conditions include those described herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

In certain embodiments, the present invention provides a compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   A¹ is N or CH;-   A² is N(Ring A) or N—R¹;-   A³ is C(R′) or N;-   A⁴ is CH or N;-   R′ is H, C₁₋₆ aliphatic, or halogen;-   each R is independently hydrogen or an optionally substituted group    selected from C₁₋₆ aliphatic, a 3-8 membered saturated or partially    unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered    bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or    partially unsaturated monocyclic heterocyclic ring having 1-2    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-10    membered bicyclic heteroaromatic ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   each of m, n, p, q, and x is independently 0, 1, or 2;-   each of y and z is independently 0, 1, 2, 3 or 4;-   each of R¹ and R² is independently R, or:    -   two R¹ groups are optionally taken together to form ═O;    -   two R² groups are optionally taken together to form ═O;    -   two R¹ groups are optionally taken together to form a covalent        bond or a bivalent C₁₋₄ alkylene chain; or    -   two R² groups are optionally taken together to form a covalent        bond or a bivalent C₁₋₄ alkylene chain;    -   an R¹ group and Ring A are optionally taken together with their        intervening atoms to form a 5-8 membered fused ring having 0-2        heteroatoms independently selected from nitrogen, oxygen or        sulfur; or    -   an R² group and Ring B are optionally taken together with their        intervening atoms to form a 5-8 membered fused ring having 0-2        heteroatoms independently selected from nitrogen, oxygen or        sulfur;-   each of R³ is independently R, halogen, —OR, —CN, or two R³ groups    are optionally taken together with their intervening atoms to form a    5-8 membered partially unsaturated or aryl fused ring having 0-2    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   R⁴ is hydrogen or an optionally substituted C₁₋₆ aliphatic group;-   Ring A is absent or an optionally substituted ring selected from    6-membered aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl    with 1-4 heteroatoms independently selected from nitrogen, oxygen or    sulfur, or 8-10 membered bicyclic aryl or heteroaryl with 1-4    heteroatoms independently selected from nitrogen, oxygen or sulfur;-   Ring B is an optionally substituted ring selected from 6-membered    aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl with 1-4    heteroatoms independently selected from nitrogen, oxygen or sulfur,    or 8-10 membered bicyclic aryl or heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, or —S(O)₂—.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₁Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R)C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂;—(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SRO, —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄₀S(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—S(O)(NR^(∘))R^(∘); —S(O)₂N═C(NR^(∘) ₂)₂; —(CH₂)₀₋₄S(O)R^(∘);—N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘);—C(NH)NR^(∘) ₂; —P(O)₂R; —P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂;—SiR^(∘) ₃; —(C₁₋₄ straight or branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄straight or branched alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may besubstituted as defined below and is independently hydrogen, C₁₋₆aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), ora 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(∘) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R¹ isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in mTORC1 activity between a samplecomprising a compound of the present invention, or composition thereof,and mTORC1, and an equivalent sample comprising mTORC1 in the absence ofsaid compound, or composition thereof.

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present inventionprovides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   A¹ is N or CH;-   A² is N(Ring A) or N—R¹;-   A³ is C(R′) or N;-   A⁴ is CH or N;-   R′ is H, C₁₋₆ aliphatic, or halogen;-   each R is independently hydrogen or an optionally substituted group    selected from C₁₋₆ aliphatic, a 3-8 membered saturated or partially    unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered    bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or    partially unsaturated monocyclic heterocyclic ring having 1-2    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-10    membered bicyclic heteroaromatic ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   each of m, n, p, q, and x is independently 0, 1, or 2;-   each of y and z is independently 0, 1, 2, 3 or 4;-   each of R¹ and R² is independently R, or:    -   two R¹ groups are optionally taken together to form ═O;    -   two R² groups are optionally taken together to form ═O;    -   two R¹ groups are optionally taken together to form a covalent        bond or a bivalent C₁₋₄ alkylene chain; or    -   two R² groups are optionally taken together to form a covalent        bond or a bivalent C₁₋₄ alkylene chain;    -   an R¹ group and Ring A are optionally taken together with their        intervening atoms to form a 5-8 membered fused ring having 0-2        heteroatoms independently selected from nitrogen, oxygen or        sulfur; or    -   an R² group and Ring B are optionally taken together with their        intervening atoms to form a 5-8 membered fused ring having 0-2        heteroatoms independently selected from nitrogen, oxygen or        sulfur;-   each of R³ is independently R, halogen, —OR, —CN, or two R³ groups    are optionally taken together with their intervening atoms to form a    5-8 membered partially unsaturated or aryl fused ring having 0-2    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   R⁴ is hydrogen or an optionally substituted C₁₋₆ aliphatic group;-   Ring A is absent or an optionally substituted ring selected from    6-membered aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl    with 1-4 heteroatoms independently selected from nitrogen, oxygen or    sulfur, or 8-10 membered bicyclic aryl or heteroaryl with 1-4    heteroatoms independently selected from nitrogen, oxygen or sulfur;-   Ring B is an optionally substituted ring selected from 6-membered    aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl with 1-4    heteroatoms independently selected from nitrogen, oxygen or sulfur,    or 8-10 membered bicyclic aryl or heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and L¹ is a    covalent bond or a C₁₋₃ bivalent straight or branched saturated or    unsaturated hydrocarbon chain wherein 1-2 methylene units of the    chain are independently and optionally replaced with —O—, —C(O)—,    —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, or —S(O)₂—.

As defined above and described herein, A¹ is N or CH. In someembodiments, A¹ is N. In some embodiments, A¹ is CH.

In some embodiments, A¹ is selected from those depicted in Table 1,below.

As defined above and described herein, A² is N(Ring A) or N—R¹.

In some embodiments, A² is N(Ring A). In some embodiments, A² is N—R¹.In some embodiments, A² is NH. In some embodiments, A² is NC(O)OC(CH₃)₃.In some embodiments, A² is NCH(CH₃)₂. In some embodiments, A² isNCH₂CF₃.

In some embodiments, A² is selected from those depicted in Table 1,below.

As defined above and described herein, each of m, and n is independently0, 1, or 2. In some embodiments, m is 0. In some embodiments, n is 0. Insome embodiments, m is 1. In some embodiments, n is 1. In someembodiments, m is 2. In some embodiments, n is 2.

As defined above and described herein, each of p, q and x isindependently 0, 1, or 2. In some embodiments, p is 0. In someembodiments, q is 0. In some embodiments, x is 0. In some embodiments, pis 1. In some embodiments, q is 1. In some embodiments, x is 1. In someembodiments, p is 2. In some embodiments, q is 2. In some embodiments, xis 2.

As defined above and described herein, each of y and z is independently0, 1, 2, 3 or 4. In some embodiments, y is 0. In some embodiments, z is0. In some embodiments, y is 1. In some embodiments, z is 1. In someembodiments, y is 2. In some embodiments, z is 2. In some embodiments, yis 3. In some embodiments, z is 3. In some embodiments, y is 4. In someembodiments, z is 4.

As defined above and described herein, A³ is C(R′) or N. In someembodiments, A³ is C(R′). In some embodiments, A³ is N.

In some embodiments, A³ is CH. In some embodiments, A³ is CCH₃. In someembodiments, A³ is CF.

In some embodiments, A³ is selected from those depicted in Table 1,below.

As defined above and described herein, A⁴ is CH or N. In someembodiments, A⁴ is CH. In some embodiments, A⁴ is N.

In some embodiments, A⁴ is selected from those depicted in Table 1,below.

As defined above and described herein, each of R¹ and R² isindependently R, or: two R¹ groups are optionally taken together to form═O; two R² groups are optionally taken together to form ═O; two R¹groups are optionally taken together to form a covalent bond or abivalent C₁₋₄ alkylene chain; two R² groups are optionally takentogether to form a covalent bond or a bivalent C₁₋₄ alkylene chain; anR¹ group and Ring A are optionally taken together with their interveningatoms to form a 5-8 membered fused ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or an R² groupand Ring B are optionally taken together with their intervening atoms toform a 5-8 membered fused ring having 0-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In some embodiments, each R¹ is hydrogen. In some embodiments R¹ ismethyl. In some embodiments, R¹ is —CH₂OH. In some embodiments, two R¹groups are optionally taken together to form ═O. In some embodiments,two R¹ groups are optionally taken together to form a covalent bond. Insome embodiments, two R¹ groups are optionally taken together to form abivalent C₁₋₄ alkylene chain. In some embodiments, a R¹ group and Ring Aare optionally taken together to form a 5-8 membered fused ring having0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments R¹ is

In some embodiments R¹ is

In some embodiments R¹ is

In some embodiments, each R² is hydrogen. In some embodiments, R² ismethyl. In some embodiments, R² is —CH₂OH. In some embodiments, two R²groups are optionally taken together to form ═O. In some embodiments,two R² groups are optionally taken together to form a covalent bond. Insome embodiments, two R² groups are optionally taken together to form abivalent C₁₋₄ alkylene chain. In some embodiments, a R² group and Ring Bare optionally taken together to form a 5-8 membered fused ring having0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, each of R¹ and R² is independently selected fromthose depicted in Table 1, below.

As defined above and described herein, each of R³ is independently R,halogen, —OR, —CN, or two R³ groups are optionally taken together withtheir intervening atoms to form a 5-8 membered fused ring having 0-2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R³ is R. In some embodiments, R³ is halogen. In someembodiments, R³ is —OR. In some embodiments, R³ is —CN. In someembodiments, two R³ groups are optionally taken together to form a 5-8membered fused ring having 0-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, R³ is methyl. In some embodiments, R³ is fluoro. Insome embodiments, R³ is chloro. In some embodiments, R³ is —OCH₃.

In some embodiments, each of R³ is selected from those depicted in Table1, below.

As defined above and described herein, R⁴ is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group. In some embodiments, R⁴ is hydrogen.In some embodiments, R⁴ is methyl. In some embodiments, R⁴ is ethyl. Insome embodiments, R⁴ is OH

As defined above and described herein, Ring A is absent or an optionallysubstituted ring selected from 6-membered aryl containing 0-2 nitrogenatoms, 5-membered heteroaryl with 1-4 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl orheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, Ring B is an optionallysubstituted ring selected from 6-membered aryl containing 0-2 nitrogenatoms, 5-membered heteroaryl with 1-4 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl orheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is,

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is selected from those depicted in Table 1,below.

As defined above and described herein, L¹ is a covalent bond or a C₁₋₃bivalent straight or branched saturated or unsaturated hydrocarbon chainwherein 1-2 methylene units of the chain are independently andoptionally replaced with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—,—N(R)—, or —S(O)₂—.

In some embodiments, L¹ is a covalent bond. In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is selected from those depicted in Table 1,below.

In some embodiments, the present invention provides a compound ofFormulae II:

or a pharmaceutically acceptable salt thereof, wherein each phenyl ringis substituted in the ortho position with a suitable monovalentsubstituent as described herein.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Exemplary Compounds

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-96

I-97

I-98

I-99

I-100

I-101

I-103

I-104

I-105

I-106

I-107

I-108

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-225

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof. Itwill be appreciated that the present invention also provides a compoundset forth in Table 1, above, as a racemic mixture, or a pharmaceuticallyacceptable salt thereof.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit mTORC1, in a biologicalsample or in a patient. In certain embodiments, the amount of compoundin compositions of this invention is such that is effective tomeasurably inhibit mTORC1, in a biological sample or in a patient. Incertain embodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of mTORC1.

The activity of a compound utilized in this invention as an inhibitor ofmTORC1, may be assayed in vitro, in vivo or in a cell line. In vitroassays include assays that determine the inhibition of mTORC1. Detailedconditions for assaying a compound utilized in this invention as aninhibitor of mTORC1 are well known to one of ordinary skill in the art.Such methods are described in detail by Liu et al., Cancer Research,73(8), Apr. 15, 2013 and Liu et al., J. Biological Chemistry, vol 287,no. 13, pp 9742-9752 (2012).

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are inhibitors of mTORC1 and are therefore useful fortreating one or more disorders associated with activity of mTORC1. Thus,in certain embodiments, the present invention provides a method fortreating an mTORC1-mediated disorder comprising the step ofadministering to a patient in need thereof a compound of the presentinvention, or pharmaceutically acceptable composition thereof.

As used herein, the terms “mTORC1-mediated” disorders, diseases, and/orconditions as used herein means any disease or other deleteriouscondition in which mTORC1, is known to play a role. Accordingly, anotherembodiment of the present invention relates to treating or lessening theseverity of one or more diseases in which mTORC1 is known to play arole. In certain embodiments, an mTORC1-mediated disorder, disease,and/or condition is selected from those described by Matt Kaeberlin,Scientifica, vol. 2013, Article ID 849186.

The methods described herein include methods for the treatment of cancerin a subject. As used in this context, to “treat” means to ameliorate orimprove at least one symptom or clinical parameter of the cancer. Forexample, a treatment can result in a reduction in tumor size or growthrate. A treatment need not cure the cancer or cause remission 100% ofthe time, in all subjects.

As used herein, the term “cancer” refers to cells having the capacityfor autonomous growth, i.e., an abnormal state or conditioncharacterized by rapidly proliferating cell growth. The term is meant toinclude all types of cancerous growths or oncogenic processes,metastatic tissues or malignantly transformed cells, tissues, or organs,irrespective of histopathologic type or stage of invasiveness. The term“tumor” as used herein refers to cancerous cells, e.g., a mass of cancercells.

Cancers that can be treated or diagnoses using the methods describedherein include malignancies of the various organ systems, such asaffecting lung, breast, thyroid, lymphoid, gastrointestinal, andgenito-urinary tract, as well as adenocarcinomas which includemalignancies such as most colon cancers, renal-cell carcinoma, prostatecancer and/or testicular tumors, non-small cell carcinoma of the lung,cancer of the small intestine and cancer of the esophagus.

In some embodiments, the methods described herein are used for treatingor diagnosing a carcinoma in a subject. The term “carcinoma” is artrecognized and refers to malignancies of epithelial or endocrine tissuesincluding respiratory system carcinomas, gastrointestinal systemcarcinomas, genitourinary system carcinomas, testicular carcinomas,breast carcinomas, prostatic carcinomas, endocrine system carcinomas,and melanomas. In some embodiments, the cancer is renal carcinoma ormelanoma. Exemplary carcinomas include those forming from tissue of thecervix, lung, prostate, breast, head and neck, colon and ovary. The termalso includes carcinosarcomas, e.g., which include malignant tumorscomposed of carcinomatous and sarcomatous tissues. An “adenocarcinoma”refers to a carcinoma derived from glandular tissue or in which thetumor cells form recognizable glandular structures.

The term “sarcoma” is art recognized and refers to malignant tumors ofmesenchymal derivation.

In some embodiments, the cancers that are treated by the methodsdescribed herein are cancers that have increased levels of mTORC1 or anincreased expression or activity of a mTORC1 relative to normal tissuesor to other cancers of the same tissues; methods known in the art anddescribed herein can be used to identify those cancers. In someembodiments, the methods include obtaining a sample comprising cells ofthe cancer, determining the mTORC1 activity in the sample, andadministering a treatment as described herein (e.g., a providedinhibitor of mTORC1). In some embodiments, the cancer is one that isshown herein to have increased levels of mTORC1 activity

In some embodiments, the present invention provides a method fortreating one or more disorders, diseases, and/or conditions wherein thedisorder, disease, or condition includes, but is not limited to, acellular proliferative disorder.

Cellular Proliferative Disorders

The present invention features methods and compositions for thediagnosis and prognosis of cellular proliferative disorders (e.g.,cancer) and the treatment of these disorders by inhibiting mTORC1activity. Cellular proliferative disorders described herein include,e.g., cancer, obesity, and proliferation-dependent diseases. Suchdisorders may be diagnosed using methods known in the art.

Cancer

Cancers include, without limitation, leukemias (e.g., acute leukemia,acute lymphocytic leukemia, acute myelocytic leukemia, acutemyeloblastic leukemia, acute promyelocytic leukemia, acutemyelomonocytic leukemia, acute monocytic leukemia, acuteerythroleukemia, chronic leukemia, chronic myelocytic leukemia, chroniclymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin'sdisease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia,multiple myeloma, heavy chain disease, and solid tumors such as sarcomasand carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, prostate cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterinecancer, testicular cancer, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma,meningioma, melanoma, neuroblastoma, and retinoblastoma). In someembodiments, the cancer is melanoma or breast cancer.

Fibrotic Diseases

Idiopathic Pulmonary Fibrosis (IPF). The PI3K pathway is activated infibrotic foci, the cardinal lesions in IPF. mTOR kinase inhibitorGSK2126458 reduces PI3K pathway signaling and functional responses inIPF-derived lung fibroblasts and mTOR inhibition reduces collagenexpression in models of IPF patients. In the bleomycin model ofpulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycinalso decreases expression of α-smooth muscle actin and fibronectin byfibroblasts in vitro.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat idiopathic pulmonary fibrosis (IPF). (See Thorax. 2016, 71(8), pp.701-11; PLoS One. 2012, 7(7)). Accordingly, in some embodiments, thepresent invention provides a method of treating idiopathic pulmonaryfibrosis (IPF), in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or pharmaceuticallyacceptable salt thereof.

Kidney Fibrosis. mTORC1 is activated in myofibroblasts, a majorpathogenic cell type in kidney fibrosis. Inhibition of mTOR withrapamycin in a murine model of kidney fibrosis (UUO), attenuatedexpression of markers of fibrosis and tubulointerstitial damage.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat kidney fibrosis. (See J Am Soc Nephrol 2013, 24, pp. 1114-1126;Kidney International 2006, 69, pp. 2029-2036; PLoS 2012, 7, Issue 3,e33626; Clin Invest Med 2014, Vol 37, no 3, E142). Accordingly, in someembodiments, the present invention provides a method of treating kidneyfibrosis, in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or pharmaceuticallyacceptable salt thereof.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat scleroderma. (See J Invest Dermatol. 2015 November; 135(11):2873-6). Accordingly, in some embodiments, the present inventionprovides a method of treating scleroderma, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor pharmaceutically acceptable salt thereof.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat hypertrophic scarring and keloid disease. (See Am J Pathol. 2012November; 181(5): 1642-58). Accordingly, in some embodiments, thepresent invention provides a method of treating hypertrophic scarringand keloid disease, in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or pharmaceuticallyacceptable salt thereof.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat cardiac fibrosis. (See J Mol Cell Cardiol. 2016 February; 91:6-9). Accordingly, in some embodiments, the present invention provides amethod of treating cardiac fibrosis, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor pharmaceutically acceptable salt thereof.

Other Proliferative Diseases

Other proliferative diseases include, e.g., obesity, benign prostatichyperplasia, psoriasis, abnormal keratinization, lymphoproliferativedisorders (e.g., a disorder in which there is abnormal proliferation ofcells of the lymphatic system), chronic rheumatoid arthritis,arteriosclerosis, restenosis, and diabetic retinopathy. Proliferativediseases that are hereby incorporated by reference include thosedescribed in U.S. Pat. Nos. 5,639,600 and 7,087,648.

Other Disorders

Other disorders include lysosomal storage diseases, including but notlimited to Pompe disease, Gaucher disease, mucopolysaccharidosis,multiple sulfatase deficiency; neurodegenerative diseases such asParkinson's disease, Alzheimer's disease, Huntington's disease,alphal-anti-trypsin deficiency, and spinal bulbar muscular atrophy. Thepresent invention provides compounds that were shown to causetranslocation of TFEB to the nucleus. TFEB translocation to the nucleuspromotes exocytosis and/or cellular clearance of accumulating substratesin the above-mentioned diseases.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat asthma. (See Respirology 2015 October; 20(7): 1055-65).Accordingly, in some embodiments, the present invention provides amethod of treating asthma, in a patient in need thereof, comprising thestep of administering to said patient a provided compound orpharmaceutically acceptable salt thereof.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat a lysosomal storage disease. (See Annals of the New York Academyof Sciences, 2016, Volume 1371, Issue 1, pp. 3-14; Hum Mol Genet. 2015,24(20), pp. 5775-88; EMBO Mol Med. 2013, 5(5), pp. 691-706; Medina, D.L., et al., Dev Cell. 2011 Sep. 13, 21(3), pp. 421-30). Accordingly, insome embodiments, the present invention provides a method of treating alysosomal storage disease, in a patient in need thereof, comprising thestep of administering to said patient a provided compound orpharmaceutically acceptable salt thereof.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat Parkinson's disease. (See Proc Natl Acad Sci USA. 2013,110(19):E1817-26). Accordingly, in some embodiments, the presentinvention provides a method of treating Parkinson's disease, in apatient in need thereof, comprising the step of administering to saidpatient a provided compound or pharmaceutically acceptable salt thereof.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat Alzheimer's disease. (See EMBO Mol Med. 2014, 6(9), pp. 1142-60).Accordingly, in some embodiments, the present invention provides amethod of treating Alzheimer's disease, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor pharmaceutically acceptable salt thereof.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat Huntington's disease. (See Sci Transl Med. 2012, 4(142):142ra97).Accordingly, in some embodiments, the present invention provides amethod of treating Huntingtons's disease, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor pharmaceutically acceptable salt thereof.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat alphal-anti-trypsin deficiency. (See EMBO Mol Med. 2013, 5(3), pp.397-412). Accordingly, in some embodiments, the present inventionprovides a method of treating alphal-anti-trypsin deficiency, in apatient in need thereof, comprising the step of administering to saidpatient a provided compound or pharmaceutically acceptable salt thereof.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat spinal bulbar muscular atrophy. (See Nat Neurosci. 2014, 17(9),pp. 1180-9). Accordingly, in some embodiments, the present inventionprovides a method of treating spinal bulbar muscular atrophy, in apatient in need thereof, comprising the step of administering to saidpatient a provided compound or pharmaceutically acceptable salt thereof.

The present invention provides compounds that are inhibitors of mTORC1activity and were shown to selectively inhibit mTORC1 over mTORC2 asmeasured by pS6K inhibition (a measure of mTORC1 activity) and pAKTactivation (a measure of mTORC2 activity). In some embodiments, aprovided compound inhibits mTORC1 selectively over mTORC2. In someembodiments, a provided compound does not measurably inhibit mTORC2. Insome embodiments, a provided compound has a pAKT activation IC₅₀ of >10μM. In some embodiments, a provided compound inhibits mTORC1with >10-fold selectivity over mTORC2. In some embodiments, a providedcompound inhibits mTORC1 with >20-fold selectivity over mTORC2. In someembodiments, a provided compound inhibits mTORC1 with >50-foldselectivity over mTORC2. In some embodiments, a provided compoundinhibits mTORC1 with >100-fold selectivity over mTORC2. In someembodiments, a provided compound inhibits mTORC1 with >150-foldselectivity over mTORC2. In some embodiments, a provided compoundinhibits mTORC1 with >200-fold selectivity over mTORC2. In someembodiments, a provided compound inhibits mTORC1 with >500-foldselectivity over mTORC2. In some embodiments, a provided compoundinhibits mTORC1 with >1,000-fold selectivity over mTORC2. Accordingly,in some embodiments, the present invention provides a method of treatinga disorder associate with mTORC1 comprising administering to patient acompound that inhibits mTORC1 wherein said compound does not inhibitmTORC2. Such compounds may be employed for indications where rapamycinand rapalogs demonstrated a benefit either in animal models or in ahuman disease setting. Such indications include:

Treatment of Metabolic Disease (Obesity and Insulin Resistance in Type 2Diabetes). Inhibition of mTORC1 pathway leads to extension of life spanin yeast, fly and mouse, and caloric restriction improves longevity andinsulin sensitivity. The underlying mechanism has been proposed tofunction by regulation of mTORC1 activation. Rapamycin-induced insulinresistance has been shown to be mediated by inhibition of mTORC2 andselective mTORC1 inhibitor is predicted to improve insulin sensitivityand glucose homeostasis.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat metabolic disease (obesity and insulin resistance in type 2diabetes). (See J Gerontol A Biol Sci Med Sci 2015, 70 (4), pp. 410-20;Aging Cell 2014, 13 (2), pp. 311-9; Diabetologia 2016, 59(3), pp.592-603; Science 2012, 335, pp. 1638-1643). Accordingly, in someembodiments, the present invention provides a method of treatingmetabolic disease (obesity and insulin resistance in type 2 diabetes),in a patient in need thereof, comprising the step of administering tosaid patient a provided compound or pharmaceutically acceptable saltthereof.

Neurofibromatosis. Neurofibromatosis type 1 (NF1) is caused by mutationsin the NF1 gene. Its protein product, neurofibromin, functions as atumor suppressor and ultimately produces constitutive upregulation ofmTOR. mTOR inhibitors have been shown to reduce tumor size and induceanti-proliferative effect in NF1-associated plexiform neurofibroma.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat neurofibromatosis. (See Curr Neurol Neurosci Rep. 2012 Jun. 12(3),pp. 294-301; Oncotarget. 2016 Jan. 31). Accordingly, in someembodiments, the present invention provides a method of treatingneurofibromatosis, in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or pharmaceuticallyacceptable salt thereof.

Cardiomyopathy and skeletal muscle dystrophy, Emery-Dreifuss musculardystrophy model (LMNA^(−/−)). Mutations in LMNA result in several humandiseases including limb-girdle muscular dystrophy (LGMD1B),Emery-Dreifuss muscular dystrophy (EDMD2/3), dilated cardiomyopathy(DCM) and conduction-system disease (CMD1A), lipodystrophy,Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome(HGPS). Lmna^(−/−) mice have elevated mTORC1 activity and short-termtreatment with rapamycin in Lmna^(−/−) mice results in reduced mTORC1signaling, improved cardiac and skeletal muscle function and enhancedsurvival by ˜50%.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat cardiomyopathy and skeletal muscle dystrophy. (See Sci Transl Med.2012, 4(144):144ra103; Handb Clin Neurol. 2013, 113, pp. 1367-76).Accordingly, in some embodiments, the present invention provides amethod of treating cardiomyopathy and skeletal muscle dystrophy, in apatient in need thereof, comprising the step of administering to saidpatient a provided compound or pharmaceutically acceptable salt thereof.

Leigh syndrome. Ndufs4 knockout (KO) mice are used as a model of Leighsyndrome and exhibit hyperactivation of mTORC1 and metabolic defects.Treatment of Ndufs4 KO mice with rapamycin extended lifespan, improvemetabolic and neurological defect associated with this disease.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat Leigh syndrome. (See Science 2013, 342(6165), pp. 1524-8).Accordingly, in some embodiments, the present invention provides amethod of treating Leigh syndrome, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor pharmaceutically acceptable salt thereof.

Oncology. Inhibition of mTOR with rapalogs has been shown to haveantitumor activity in murine cancer models and in cancer patients.Examples of sensitive cancer types include, but are not limited to,hepatocellular carcinoma, breast cancers, mantle cell lymphomas, lungcarcinoma, tuberous sclerosis and lymphangioleiomyomatosis.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat cancer and oncologic disorders. (See Trends Cancer 2016; Inpress). Accordingly, in some embodiments, the present invention providesa method of treating cancer and oncologic disorders, in a patient inneed thereof, comprising the step of administering to said patient aprovided compound or pharmaceutically acceptable salt thereof.

Non-alcoholic steatohepatitis (NASH). The present invention providesinhibitors that induce autophagy to clear degraded cytoplasmic proteins,and NASH disease is characterized by lipid deposits, inflammation andfibrosis in the liver. The inhibition of mTORC1 pathway induce autophagyand down regulate SREBP-1 to decrease lipid biosynthesis to reduce lipidstorage.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat non-alcoholic steatohepatitis (NASH). (See J Clin Exp Hepatol2014; 4(1), pp. 51-9). Accordingly, in some embodiments, the presentinvention provides a method of treating non-alcoholic steatohepatitis(NASH), in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or pharmaceuticallyacceptable salt thereof.

Tuberous sclerosis (TSC) and lymphangioleiomyomatosis (LAM). Failure inthe regulation of mTOR is critical to the pathogenesis of the inheriteddisorder tuberous sclerosis complex (TSC) and the related lung disease,lymphangioleiomyomatosis (LAM). Both diseases are caused by mutations ofTSC1 or TSC2 leading to inappropriate activity of signaling downstreamof mTORC1. TSC patients develop nonmalignant tumors in many organs,including the brain, while LAM patients, mostly women, accumulateabnormal, muscle-like cells in certain organs or tissues, especially thelungs, lymph nodes, and kidneys. The rapalogs, Everolimus and Sirolimus,are currently approved for the treatment of both TSC and LAM,respectively, by the US FDA.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat tuberous sclerosis and lymphangioleiomyomatosis. (See J. Clin.Invest. 2011, 121, pp. 1231-1241; J. Clin Epidemiol. 2015, 7, pp.249-57). Accordingly, in some embodiments, the present inventionprovides a method of treating tuberous sclerosis andlymphangioleiomyomatosis, in a patient in need thereof, comprising thestep of administering to said patient a provided compound orpharmaceutically acceptable salt thereof.

Senescence and diseases of aging. Rapamycin suppresses the mammalianTORCI complex, which regulates translation, and extends lifespan indiverse species, including mice. Rapamycin was shown to inhibit thepro-inflammatory phenotype of senescent cells. As senescent cellsaccumulate with age, the senescence-associated secretory phenotype(SASP) can disrupt tissues and contribute to age-related pathologies,including cancer. Inhibition of mTOR suppressed the secretion ofinflammatory cytokines by senescent cells. Rapamycin reduced cytokinelevels including IL6 and suppressed translation of the membrane-boundcytokine IL1A. Reduced IL1A diminishes NF-κB transcriptional activity,which controls the SASP. Thus, mTORC1 inhibitors might ameliorateage-related pathologies, including late-life cancer, by suppressingsenescence-associated inflammation.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat senescence and diseases of aging. (See Nature Cell Biology 17,2015, pp. 1049-1061; Free Radic Biol Med. 2016 June; 95:133-54).Accordingly, in some embodiments, the present invention provides amethod of treating senescence and diseases of aging, in a patient inneed thereof, comprising the step of administering to said patient aprovided compound or pharmaceutically acceptable salt thereof.

Additional therapeutic indications where mTORC inhibition may bebeneficial are: cardiovascular disease (acute coronary syndrome),coronary occlusions with eluting stents, polycystic kidney disease,neurofibromatosis, epilepsy assoc. with TSC1 and/or TSC2 mutations,polycystic liver, pachyonychia congenital, fragile x syndrome, Friedrichataxia, Peutz-Jeghers syndrome, eye disease including neovascularage-related macular degeneration, uveitis, diabetic macular edema,fibroblast growth including pulmonary fibrosis, renalinsufficiency/fibrosis, metabolic syndrome, diseases of the immunesystem including immune senescence, lupus nephritis, chronic immunethrombocytopenia, multiple sclerosis, cancer including lymphoma, tumorsassociated with TSC1/2 mutations, angiomyolipoma assoc. with TSC1/2mutations, breast cancer, hepatocellular cancer, leukemia, glioma,adenoid cystic carcinoma, senescence, autism, and vascular rheumatoidarthritis.

In some embodiments, the method of inhibiting mTORC1 activity is used totreat cardiovascular disease (acute coronary syndrome), coronaryocclusions with eluting stents, polycystic kidney disease,neurofibromatosis, epilepsy assoc. with TSC1 and/or TSC2 mutations,polycystic liver, pachyonychia congenital, fragile x syndrome, Friedrichataxia, Peutz-Jeghers syndrome, eye disease including neovascularage-related macular degeneration, uveitis, diabetic macular edema,fibroblast growth including pulmonary fibrosis, renalinsufficiency/fibrosis, metabolic syndrome, diseases of the immunesystem including immune senescence, lupus nephritis, chronic immunethrombocytopenia, multiple sclerosis, cancer including lymphoma, tumorsassociated with TSC1/2 mutations, angiomyolipoma assoc. with TSC1/2mutations, breast cancer, hepatocellular cancer, leukemia, glioma,adenoid cystic carcinoma, senescence, autism, and vascular rheumatoidarthritis. Accordingly, in some embodiments, the present inventionprovides a method of treating cardiovascular disease (acute coronarysyndrome), coronary occlusions with eluting stents, polycystic kidneydisease, neurofibromatosis, epilepsy assoc. with TSC1 and/or TSC2mutations, polycystic liver, pachyonychia congenital, fragile xsyndrome, Friedrich ataxia, Peutz-Jeghers syndrome, eye diseaseincluding neovascular age-related macular degeneration, uveitis,diabetic macular edema, fibroblast growth including pulmonary fibrosis,renal insufficiency/fibrosis, metabolic syndrome, diseases of the immunesystem including immune senescence, lupus nephritis, chronic immunethrombocytopenia, multiple sclerosis, cancer including lymphoma, tumorsassociated with TSC1/2 mutations, angiomyolipoma assoc. with TSC1/2mutations, breast cancer, hepatocellular cancer, leukemia, glioma,adenoid cystic carcinoma, senescence, autism, and vascular rheumatoidarthritis, in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or pharmaceuticallyacceptable salt thereof.

In some embodiments, the present invention is an inhibitor of members ofthe glucose transporter (GLUT) family. In some embodiments, the presentinvention is a pan-glucose inhibitor, inhibiting GLUT subtypes 1, 2, 3,4, and 5. In some embodiments, the present invention is an inhibitor ofone or more GLUT subtypes, individually or severally.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

In other embodiments, the present invention provides a method fortreating a disorder mediated by mTORC1 in a patient in need thereof,comprising the step of administering to said patient a compoundaccording to the present invention or pharmaceutically acceptablecomposition thereof. Such disorders are described in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD 181461from Pfizer and leucovorin. The term “aromatase inhibitor” as usedherein relates to a compound which inhibits estrogen production, forinstance, the conversion of the substrates androstenedione andtestosterone to estrone and estradiol, respectively. The term includes,but is not limited to steroids, especially atamestane, exemestane andformestane and, in particular, non-steroids, especiallyaminoglutethimide, roglethimide, pyridoglutethimide, trilostane,testolactone, ketokonazole, vorozole, fadrozole, anastrozole andletrozole. Exemestane is marketed under the trade name Aromasin™.Formestane is marketed under the trade name Lentaron™. Fadrozole ismarketed under the trade name Afema™. Anastrozole is marketed under thetrade name Arimidex™. Letrozole is marketed under the trade namesFemara™ or Femar™. Aminoglutethimide is marketed under the trade nameOrimeten™. A combination of the invention comprising a chemotherapeuticagent which is an aromatase inhibitor is particularly useful for thetreatment of hormone receptor positive tumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporine derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aP13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS—7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF—I 126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S—001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; othergeldanamycin related compounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

List of common abbreviations used in the experimental section.

-   -   4A MS: 4 Å molecular sieves    -   AcOH: acetic acid    -   Anhyd: anhydrous    -   aq: aqueous    -   BH₃-THF: borane tetrahydrofuran complex    -   BINAP: (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)    -   Bn: benzyl    -   Boc: tert-butoxycarbonyl    -   (Boc)₂O: di-tert-butyl dicarbonate    -   BrettPhos:        2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl    -   CbzCl: benzyl chloroformate    -   Cbz-OSU: N-(Benzyloxycarbonyloxy)succinimide    -   CHIRAL-HPLC: chiral high performance liquid chromatography    -   CMBP: (cyanomethylene)tributylphosphorane    -   Conc.: concentrated    -   CuCN: copper cyanide    -   d: days    -   DAST: diethylaminosulfur trifluoride    -   DavePhos: 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl    -   dba: dibenzylideneacetone    -   DBU: 1,8-diazobicyclo[5.4.0]undec-7-ene    -   DCE: 1,2-dichloroethane    -   DCM: dichloromethane    -   DEA: diethylamine    -   DIBAL-H: diisobutylaluminium hydride    -   DIPEA: N,N-diisopropylethylamine    -   DMA: N,N-dimethylacetamide    -   DMAP: 4-dimethylaminopyridine    -   DMF: N,N-dimethylformamide    -   DMPU: 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone    -   DMSO: dimethyl sulfoxide    -   DPPA: diphenylphosphoryl azide    -   dppf: 1,1′-bis(diphenylphosphino)ferrocene    -   EA: ethyl acetate    -   EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide        hydrochloride    -   EDTA: ethylenediaminetetraacetic acid    -   ee: enantiomeric excess    -   ESI: electrospray ionization    -   Et₃N: triethylamine    -   Et₂O: diethyl ether    -   EtOAc: ethyl acetate    -   EtOH: ethanol    -   Fmoc: fluorenylmethyloxycarbonyl    -   Fmoc-OSu: N-(9-fluorenylmethoxycarbonyloxy)succinimide    -   h: hours    -   HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium        hexafluorophosphate    -   HOBT: Hydroxybenzotriazole    -   HPLC: high performance liquid chromatography    -   HCl: hydrochloric acid    -   IBX: 2-iodoxybenzoic acid    -   IPA: isopropyl alcohol    -   JackiePhos:        2-{Bis[3,5-bis(trifluoromethyl)phenyl]phosphino}-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,        Bis(3,5-bis(trifluoromethyl)phenyl)(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine    -   LDA: lithium diisopropylamide    -   M: molar    -   mCPBA: meta-chloroperoxybenzoic acid    -   Me: methyl    -   MeCN: acetonitrile    -   MeOH: methanol    -   MgO: magnesium oxide    -   min: minutes    -   mL: milliliters    -   mM: millimolar    -   mmol: millimoles    -   MOM: methoxymethyl    -   MsCl: Mesyl Chloride    -   MTBE: methyl tert-butyl ether    -   NMP: N-methyl-2-pyrrolidone    -   n-BuLi: n-butyl lithium    -   NBS: N-bromosuccinimide    -   NIS: N-iodosuccinimide    -   NMO: 4-methylmorpholine N-oxide    -   NMP: N-methylpyrrolidine    -   NMR: Nuclear Magnetic Resonance    -   ° C.: degrees Celsius    -   PBS: phosphate buffered saline    -   Pd/C: palladium on carbon    -   Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(O)    -   PE: petroleum ether    -   prep-HPLC: preparative high performance liquid chromatography    -   P(o-tol)₃: tri(o-tolyl)phosphine    -   PTFE: polytetrafluoroethylene    -   Rel: relative    -   rt: room temperature    -   RuPhos: 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl    -   sat: saturated    -   SFC: supercritical fluid chromatography    -   SGC: silica gel chromatography    -   STAB: sodium triacetoxyborohydride    -   TBAB: Tetra-n-butylammonium bromide    -   TBAF: Tetra-n-butylammonium fluoride    -   TBSCl: tert-Butyldimethylsilyl chloride    -   tBuOK: potassium tert-butoxide    -   tBuONa: sodium tert-butoxide    -   TEA: triethylamine    -   TEBAC: Benzyltriethylammonium chloride    -   Tf: trifluoromethanesulfonate    -   TfAA: trifluoromethanesulfonic anhydride    -   TFA: trifluoracetic acid    -   TIPS: triisopropylsilyl    -   TLC: thin layer chromatography    -   THF: tetrahydrofuran    -   TMSCN: trimethylsilyl cyanide    -   pTSA: para-toluenesulfonic acid    -   TsOH: p-Toluenesulfonic acid    -   XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene    -   XPhos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl        LCMS Methods

Samples were analyzed by LCMS using the following methods:

Method A: SunFire™ C18, 4.6*50 mm, 3.5 um column Xbridge C18 3.5μm4.6×50 mm column. The elution system used was a gradient of 5%-95%over 1.5 min at 2 ml/min and the solvent was acetonitrile/0.01% aqueousTFA.

Method B: Xbridge C18 3.5 m4.6×50 mm column, the elution system used wasa gradient of 5%-95% over 1.5 min at 2 ml/min and the solvent wasacetonitrile/10 mM ammonium acetate aqueous solution.

Samples were also analyzed using the following LCMS methods:

TABLE 2 LCMS Method 1 Column Kinetex Core-Shell C18 Part No. 00B-4601-AN2.1 × 50 mm, 5 μm Column Temp 40° C. Mobile Phase A, Water + 0.1% Formicacid B, Acetonitrile + 0.1% Formic acid Gradient Time (mins) % organic0.00 5 1.20 100 1.30 100 1.31 5 Flow rate 1.2 ml/min Injection Vol 3 μlDetection Signal UV 215 PDA Spectrum Range: 210-420 nm step: 1 nm (NotMS14 this has single wavelength detector) MSD Signal Scan Pos(Shimadzu): 100-1000 settings Scan Pos (MS14): 130-850 Scan Pos (MS11):150-850

TABLE 3 LCMS Method 2 Column Supelco Ascentis Express Part No. 53802-U2.1 × 30 mm, 2.7 μm Column Temp 40° C. Mobile Phase A, Water + 0.1%Formic acid B, Acetonitrile + 0.1% Formic acid Gradient Time (mins) %organic 0 5 1.5 100 1.6 100 1.61 5 Flow rate 1 ml/min Injection Vol 3 μlDetection Signal UV 215 PDA Spectrum Range: 210-420 nm step: 1 nm (NotMS14 this has single wavelength detector) MSD Signal Scan Pos(Shimadzu): 100-1000 settings Scan Pos (MS14): 130-850 Scan Pos (MS11):150-850

TABLE 4 LCMS Method 3 Column Waters Atlantis dC18 Part No. 186001291 2.1× 50 mm, 3 μm Column Temp 40° C. Mobile Phase A, Water + 0.1% Formicacid B, Acetonitrile + 0.1% Formic acid Gradient Time (mins) % organic0.00 5 2.50 100 2.70 100 2.71 5 3.50 5 Flow rate 1 ml/min Injection Vol3 μl Detection Signal UV 215 PDA Spectrum Range: 210-420 nm step: 1 nm(Not MS14 this has single wavelength detector) MSD Signal Scan Pos(MS14): 130-850 settings

TABLE 5 LCMS Method 4 Column Phenomenex Gemini-NX C18 00B-4453-B0 2.0 ×50 mm, 3 um Column Temp 40° C. Mobile Phase A, 2 mM amm. bicarbonate,buffered to pH10 B, Acetonitrile Gradient Time (mins) % organic 0.00 11.80 100 2.10 100 2.30 1 3.50 1 Flow rate 1 ml/min Injection Vol 3 μlDetection Signal UV 215 PDA Spectrum Range: 210-420 nm step: 1 nm (NotMS14 this has single wavelength detector) MSD Signal Scan Pos (MS10):150-850 settings Scan Pos (MS14): 130-850

TABLE 6 LCMS Method 5 Column Waters Atlantis dC18 Part No. 186001295 2.1× 100 mm, 3 μm Column Temp 40° C. Mobile Phase A, Water + 0.1% Formicacid B, Acetonitrile + 0.1% Formic acid Gradient Time (mins) % organic0.00 5 5.00 100 5.40 100 5.42 5 7.00 5 Flow rate 0.6 ml/min InjectionVol 3 μl Detection Signal UV 215 PDA Spectrum Range: 210-420 nm step: 1nm MSD Signal Scan Pos (Shimadzu): 100-1000 settings Scan Pos (MS11):150-850

TABLE 7 LCMS Method 6 Column Phenomenex Gemini-NX C18 Part No.00D-4453-B0 2.0 × 100 mm, 3 μm column Column Temp 40° C. Mobile Phase A,2 mM amm. bicarbonate, buffered to pH10 B, Acetonitrile Gradient Time(mins) % organic 0.00 5 5.50 100 5.90 100 5.92 5 7.00 5 Flow rate 0.5ml/min Injection Vol 3 μl Detection Signal UV 215 PDA Spectrum Range:210-420 nm step: 1 nm (Not MS14 this has single wavelength detector) MSDSignal Scan Pos (MS10): 150-850 settings Scan Pos (MS14): 130-850

TABLE 9 LCMS Method 8 Column Waters SymmetryShield RP8 Part No.WAT094257 2.1 × 50 mm, 3.5 μm Column Temp 40° C. Mobile Phase A, Water +0.1% Formic acid B, Acetonitrile + 0.1% Formic acid Gradient Time (mins)% organic 0.00 5 2.20 100 2.70 100 2.71 5 Flow rate 1 ml/min InjectionVol 3 μl Detection Signal UV 215 PDA Spectrum Range: 210-420 nm step: 1nm MSD Signal Scan Pos: 100-1000 settings

TABLE 8 LCMS Method 7 Column Phenomenex Kinetix-XB C18 Part No.00D-4498-AN 2.1 × 100 mm, 1.7 μm Column Temp 40° C. Mobile Phase A,Water + 0.1% Formic acid B, Acetonitrile + 0.1% Formic acid GradientTime (mins) % organic 0.00 5 5.30 100 5.80 100 5.82 5 7.00 5 Flow rate0.6 ml/min Injection Vol 1 μl Detection Signal UV 215 PDA SpectrumRange: 200-400 nm step: 1 nm MSD Signal Scan Pos: 150-850 settings

TABLE 10 LCMS Method 9 Column Phenomenex Gemini-NX C18 Part No.00D-4453-B0 2.0 × 100 mm, 3 μm column Column Temp 40° C. Mobile Phase A,2 mM amm. bicarbonate, buffered to pH10 B, Acetonitrile Gradient Time(mins) % organic 0.00 5 5.50 100 5.90 100 5.92 5 7.00 5 Flow rate 0.6ml/min Injection Vol 3 μl Detection Signal UV 215 PDA Spectrum Range:210-420 nm step: 1 nm (Not MS14 this has single wavelength detector) MSDSignal Scan Pos (MS10): 150-850 settings Scan Pos (MS14): 130-850Purification Methods

Samples were purified via preparative HPLC using the following methods:Method C: the crude samples were dissolved in DMF otherwise noted beforepurified. Boston C18 21*250 mm 10 μm column. The mobile phase wasacetonitrile/0.01% aqueous TFA (or 0.01% aqueous HCl).

Method D: the crude samples were dissolved in DMF otherwise noted beforepurified. Boston C18 21*250 mm 10 μm column. The mobile phase wasacetonitrile/10 mM ammonium acetate aqueous solution.

Samples were also purified via preparative HPLC using the followingmethods:

TABLE 11 Generic UV-Directed High pH prep method Column Waters XbridgeC18 Part no. 186003930 30 × 100 mm, 10 um Column Temp Room temperatureMobile Phase A, Water + 0.2% Ammonium hydroxide B, Acetonitrile + 0.2%Ammonium hydroxide Gradient Time (mins) % organic 0 10 0.55 10 14.44 9516.55 95 16.75 10 Flow rate 40 ml/min Injection Vol 1500 μl DetectionSignal UV 215

TABLE 12 Generic UV-Directed low pH prep method Column Waters SunfireC18 Part no. 186003971 30 × 100 mm, 10 um Column Temp Room temperatureMobile Phase A, Water + 0.1% Formic acid B, Acetonitrile + 0.1% Formicacid Gradient Time (mins) % organic 0 10 0.55 10 14.44 95 16.55 95 16.7510 Flow rate 40 ml/min Injection Vol 1500 μl Detection Signal UV 215

Amide Coupling using HATU Generic Method A.

A solution of amine (1.0 eq), acid (1.2 eq), HATU (1.05 eq) andDIPEA(3.0 eq) were dissolved in DMF and stirred at rt for 17 h. Themixture was extracted with EtOAc, the organic layer was concentrated.The residue was purified by column chromatography or prep-HPLC to obtainthe target compounds.

Amide Coupling using EDCI/HOBT Generic Method B.

The acid (1.2 eq) was dissolved in DMF, and then EDCI (2.0 eq) and HOBT(1.5 eq) were added and stirred at rt for 1 h. Then corresponding amine(1.0 eq) was added. The mixture was stirred at rt for 18 h. The solutionwas purified via preparative HPLC to obtain the target compounds.

Intermediates:

[Intermediate1]—5-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic

Methyl 5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoate[Intermediate 5] (87%, 2.5 g, 6.0 mmol) was suspended in 4:1methanol/water (20 ml). 2M. aq. LiOH (12 ml) was added and the reactionwas heated at 65° C. for 2 h. The reaction was concentrated in vacuo.The concentrated aqueous solution was diluted with water (30 ml),acidified to pH 5 and extracted with EtOAc (4×30 ml). The combinedorganics were washed with sat aq NaHCO₃ (30 ml) and concentrated invacuo to give 2.3 g of the crude product as a pale yellow solid. Thesolid was purified via flash column chromatography (gradient from 0% to10% MeOH in DCM). The fractions containing product were combined andconcentrated in vacuo to afford the title compound as a cream solid(1.70 g, 81%). ¹H NMR (250 MHz, DMSO-d6) δ 12.41 (s, 1H), 7.68 (dd,J=7.7, 1.5 Hz, 1H), 7.64-7.53 (m, 1H), 7.19 (d, J=8.2 Hz, 1H), 7.11 (s,1H), 7.07 (t, J=7.5 Hz, 1H), 6.90 (s, 1H), 4.55 (s, 1H), 3.52 (d, J=12.4Hz, 3H), 2.98 (t, J=11.0 Hz, 2H), 2.35 (s, 3H), 2.12 (s, 3H), 2.10-2.00(m, 2H), 1.71 (d, J=10.5 Hz, 2H). LCMS Method 2—Tr=1.25 min (ES+) (M+H)+350.2.

[Intermediate 2]—Methyl 5-amino-2,4-dimethylbenzoate

Methyl 2,4-dimethyl-5-nitrobenzoate (2 g, 9.56 mmol) was suspended in amixture of 4:1 ethanol/water (60 ml) then ammonium chloride (0.56 g,10.52 mmol) and iron powder (1.87 g, 33.46 mmol) were added and thereaction was stirred at 80° C. for 1 h. The mixture was cooled to rt andfiltered through Celite using EtOAc. The filtrate was concentrated invacuo to yield crude title compound as a cream solid (2.171 g, 127%). ¹HNMR (250 MHz, DMSO-d6) δ 7.15 (s, 1H), 6.85 (s, 1H), 4.89 (s, 2H), 3.76(s, 3H), 2.32 (s, 3H), 2.06 (s, 3H). LCMS Method 2—Tr=0.88 min (ES+)(M+H)+ 180.0.

[Intermediate 3]—2-(4-Hydroxypiperidin-1-yl)benzonitrile

A suspension of 2-fluorobenzonitrile (1 g, 8.257 mmol), piperidin-4-ol(1.25 g, 12.39 mmol) and K₂CO₃ (2.28 g, 16.51 mmol) in DMF (10 ml) washeated at 130° C. for 18 h. The cooled reaction mixture was diluted withwater (30 ml) and EtOAc (30 ml) then the phases were separated. Theaqueous phase was extracted with EtOAc (3×30 ml) and the combinedorganics were washed with brine (3×20 ml), dried (MgSO₄) and filtered.The filtrate was concentrated in vacuo to yield the title compound as abrown viscous oil (1.80 g, 97%). ¹H NMR (500 MHz, Chloroform-d) δ 7.54(dd, J=7.7, 1.5 Hz, 1H), 7.49-7.42 (m, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.97(t, J=7.5 Hz, 1H), 3.90 (tt, J=8.0, 3.9 Hz, 1H), 3.46 (dt, J=10.4, 4.2Hz, 2H), 3.01 (ddd, J=12.1, 9.0, 3.0 Hz, 2H), 2.07 (ddt, J=12.3, 6.3,3.2 Hz, 2H), 1.80 (dtd, J=12.6, 8.6, 3.6 Hz, 2H).

LCMS Method 3—Tr=1.39 min (ES+) (M+H)+ 203

[Intermediate 4]—2-(4-Oxopiperidin-1-yl)benzonitrile

To a solution of 2-(4-hydroxypiperidin-1-yl)benzonitrile [Intermediate3] (300 mg, 1.48 mmol) in DCM (5 ml) at 0° C. was added Dess-Martinperiodinane (944 mg, 2.23 mmol) and the reaction was stirred at rt for 2h. 2M. aq. NaOH (10 ml) was added to the reaction mixture with stirringfor 10 min. DCM (10 ml) was added and the phases separated. The aqueousphase was extracted with DCM (3×15 ml) and the combined organic extractswere washed with brine (30 ml) and then concentrated in vacuo to yieldthe title compound as a brown viscous oil (300 mg, 72%). ¹H NMR (500MHz, Chloroform-d) δ 7.61 (dd, J=7.7, 1.6 Hz, 1H), 7.54-7.49 (m, 1H),7.09-7.04 (m, 2H), 3.52 (t, J=6.1 Hz, 4H), 2.69 (t, J=6.1 Hz, 4H). LCMSMethod 4—Tr=1.49 min (ES+) (M+H)+ 201.

[Intermediate 5]—Methyl5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoate

Methyl 5-amino-2,4-dimethylbenzoate [Intermediate 2] (2.1 g, 11.7 mmoland 2-(4-oxopiperidin-1-yl)benzonitrile [Intermediate 4] (2.84 g, 12.9mmol) were suspended in DCM (40 ml) and stirred at rt for 30 min.NaBH(OAc)₃ (2.48 g, 11.7 mmol) was then added and the reaction wasstirred for 30 min. Further NaBH(OAc)₃ (3.73 g, 17.6 mmol) was thenadded and the reaction was stirred overnight.2-(4-Oxopiperidin-1-yl)benzonitrile (91%, 0.88 g, 4 mmol) and NaBH(OAc)₃(2 g, 9.4 mmol) were added and the reaction stirred for 1 h. Thereaction mixture was diluted with water (40 ml). The organics wereseparated and the aqueous phase extracted with DCM (40 ml). The combinedorganics were concentrated in vacuo to give a brown oil. The oil waspurified via flash column chromatography using gradients from 0% to 100%EtOAc in heptane followed by 0% to 100% MeOH in EtOAc. The fractionscontaining product were combined and concentrated in vacuo to afford thetitle compound as a pale yellow solid (2.5 g, 52%). ¹H NMR (250 MHz,DMSO-d6) δ 7.68 (dd, J=7.7, 1.6 Hz, 1H), 7.59 (ddd, J=9.0, 7.5, 1.7 Hz,1H), 7.23-7.16 (m, 1H), 7.11-7.02 (m, 2H), 6.93 (s, 1H), 6.85 (s, OH),4.61 (d, J=8.1 Hz, 1H), 3.79 (s, 3H), 3.58-3.39 (m, 3H), 2.98 (t, J=10.9Hz, 2H), 2.34 (s, 3H), 2.13 (s, 4H), 2.01 (d, J=9.3 Hz, 1H), 1.82-1.62(m, 2H). LCMS Method 2—Tr=1.96 min (ES+) (M+H)+ 364.

[Intermediate 6]—tert-Butyl(2S)-4-(2-cyano-4,5-difluorophenyl)-2-methylpiperazine-1-carboxylate

2-Bromo-4,5-difluorobenzonitrile (1.0 g, 4.59 mmol), tert-butyl(2S)-2-methylpiperazine-1-carboxylate (0.96 g, 4.82 mmol), Pd₂(dba)₃(0.21 g, 0.23 mmol), XantPhos (0.27 g, 0.46 mmol) and sodiumtert-butoxide (1.32 g, 13.76 mmol) were suspended in 1,4-dioxane(20 ml)(degassed with nitrogen for 5 minutes) then the reaction was heated at100° C. for 6 h. The reaction was cooled then filtered through Celite,using DCM. The filtrate was concentrated in vacuo then the residue waspartitioned between DCM (50 ml) and water (30 ml) and the organics wereseparated, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified via flash column chromatography using gradients of0% to 100% EtOAc in heptane followed by 0% to 100% MeOH in EtOAc, thenthe fractions containing product were concentrated in vacuo to yield thetitle compound as a pale yellow oil which crystallized on standing (548mg, 35%). ¹H NMR (500 MHz, DMSO-d6) 8.04 (dd, J=10.4, 8.8 Hz, 1H), 7.32(dd, J=12.7, 7.2 Hz, 1H), 4.24 (s, 1H), 3.84 (d, J=13.2 Hz, 1H), 3.32(d, J=2.1 Hz, 2H), 3.16 (t, J=11.4 Hz, 1H), 2.90 (dd, J=12.1, 3.7 Hz,1H), 2.78 (td, J=11.9, 3.4 Hz, 1H), 1.42 (s, 9H), 1.27 (d, J=6.7 Hz,3H).

LCMS Method 2—Tr=1.28 min (ES+) (M+H⁺) 360.1

[Intermediate7]—4,5-Difluoro-2-[(3S)-3-methylpiperazin-1-yl]benzonitrile

tert-Butyl(2S)-4-(2-cyano-4,5-difluorophenyl)-2-methylpiperazine-1-carboxylate[Intermediate 6] (400 mg, 1.19 mmol) was dissolved in trifluoroaceticacid (20% in DCM) (2.5 ml) then the reaction was agitated at ambienttemperature for 4 h then concentrated in vacuo. The residue waspartitioned between DCM (15 ml) and sat. aq. NaHCO₃(15 ml) then theorganics were dried over Na₂SO₄, filtered and concentrated in vacuo toyield the title compound as a pale yellow crystalline solid (258 mg,92%). ¹H NMR (500 MHz, DMSO-d6) δ 7.99 (dd, J=10.4, 8.8 Hz, 1H), 7.27(dd, J=12.9, 7.2 Hz, 1H), 3.34 (s, 1H), 3.04-2.96 (m, 1H), 2.94-2.80 (m,2H), 2.76 (td, J=11.3, 2.5 Hz, 1H), 2.53-2.51 (m, 1H), 2.48-2.42 (m,1H), 1.02 (d, J=6.4 Hz, 3H). LCMS Method 2—Tr=0.70 min (ES+) (M+H⁺)238.45.

[Intermediate 8]—Methyl5-{[1-(2-cyanophenyl)piperidin-4-yl](methyl)amino}-2,4-dimethylbenzoate

To a suspension of methyl5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoate(60 mg,0.165 mmol) [Intermediate 5] and potassium carbonate (27 mg, 0.198 mmol)in DMF (1 mL) was added methyl iodide (10 uL, 0.165 mmol) and thereaction mixture stirred at 70° C. for 3 h. After 3 h, methyl iodide (10uL, 0.165 mmol) and potassium carbonate (27 mg, 0.198 mmol) were addedand the reaction mixture heated at 90° C. for 3 h. After 3 h, thereaction mixture was cooled to rt and partitioned between water (5 mL)and ethyl acetate (5 mL). The aqueous was extracted into ethyl acetate(3×5 mL) and the combined organic extracted washed with brine (2×10 mL)and concentrated in vacuo to afford the title compound as a yellowviscous oil(50 mg, 66%). ¹H NMR (500 MHz, Chloroform-d) δ 7.68 (s, 1H),7.54 (dd, J=8.1, 1.6 Hz, 1H), 7.49-7.41 (m, 1H), 7.07 (s, 1H), 6.99-6.96(m, 2H), 3.88 (s, 3H), 3.62-3.57 (m, 2H), 2.95-2.90 (m, 1H), 2.79 (td,J=11.7, 2.5 Hz, 2H), 2.69 (s, 3H), 2.53 (s, 3H), 2.32 (d, J=2.6 Hz, 3H),1.97-1.84 (m, 4H). LCMS Method 1—Tr=2.21 min (ES+) (M+H)+ 378.

[Intermediate9]—5-{[1-(2-Cyanophenyl)piperidin-4-yl](methyl)amino}-2,4-dimethylbenzoicacid

To a suspension of methyl5-{[1-(2-cyanophenyl)piperidin-4-yl](methyl)amino}-2,4-dimethylbenzoate(50 mg, 0.132 mmol) [Intermediate 8] and lithium hydroxide monohydrate(56 mg, 1.325 mmol) in methanol/water (3:1, 10 mL) was heated at 50° C.for 4 h. After 4 h, the reaction mixture was cooled to rt and themethanol removed in vacuo. The resultant suspension was diluted withwater (5 mL) and then acidified to pH˜1 using 4M. aq, HCl (˜5 mL). Thesolution was diluted with ethyl acetate (20 mL) and the phasesseparated. The aqueous was extracted into ethyl acetate (2×10 mL) andthe combined organic extracts were washed with brine (20 mL), dried(MgSO₄) and filtered. The filtrate was concentrated in vacuo to affordthe title compound as off-white solid (45 mg, 75%).

1H NMR (500 MHz, Chloroform-d) δ 8.06-7.89 (m, 1H), 7.54 (dd, J=7.7, 1.6Hz, 1H), 7.49-7.44 (m, 1H), 7.23 (s, 1H), 7.06-6.96 (m, 2H), 3.71-3.40(m, 3H), 3.38-2.91 (m, 3H), 2.91-2.81 (m, 2H), 2.81-2.66 (m, 2H),2.66-2.56 (m, 3H), 2.42-2.11 (m, 3H), 2.08-1.94 (m, 3H).

LCMS Method 1—Tr=1.80 min (ES+) (M+H)+ 368.

[Intermediate 10]—1-Fluoro-2-methanesulfinylbenzene

1-Fluoro-2-(methylsulfanyl)benzene (5 g, 35.16 mmol) was suspended inTHF (10 ml) at 0° C. then mCPBA (6.7 g, 38.7 mmol) was added portionwiseand the reaction was stirred at rt for 18 h. The reaction waspartitioned between aq. sodium bisulfite (10%, 20 ml) and DCM (20 ml).The aqueous layer was extracted with DCM (3×20 ml). The organics werecombined and concentrated in vacuo to afford a white solid. The whitesolid was partitioned between 2M. aq. NaOH (30 ml) and DCM (30 ml). Theorganics were washed with 2M. aq. NaOH (2×20 ml), brine (30 ml), dried(MgSO₄), filtered and concentrated in vacuo to afford the title compoundas a yellow oil (5.0 g, 69%). ¹H NMR (500 MHz, Chloroform-d) δ 7.84-7.77(m, 1H), 7.48-7.42 (m, 1H), 7.35 (t, J=7.0 Hz, 1H), 7.08 (t, J=8.7 Hz,1H), 2.80-2.76 (m, 3H). LCMS Method 3-Tr=0.82 min (ES+) (M+H)+ 159.

[Intermediate 11]—tert-ButylN-[(2-fluorophenyl)(methyl)oxo-λ⁶-sulfanylidene]carbamate

1-Fluoro-2-methanesulfinylbenzene [Intermediate 10] (5 g, 31.6 mmol),tert-butyl carbamate (7.4 g, 63.2 mmol), magnesium oxide (5.1 g, 126.4mmol) and rhodium (II) acetate (419 mg, 0.95 mmol) were suspended in DCM(20 ml). (Diacetoxyiodo)benzene (20.4 g, 63.2 mmol) was addedportionwise and the reaction was stirred at rt for 18 h. The reactionwas filtered and the filtrate was concentrated in vacuo. The residue waspurified by flash column chromatography eluting with EtOAc in heptane(0% with a gradient towards 100%). The fractions containing product werecombined and concentrated in vacuo to afford the title compound as apale yellow oil (6.5 g, 60%). ¹H NMR (250 MHz, Chloroform-d) δ 8.12-7.87(m, 1H), 7.74-7.60 (m, 1H), 7.42-7.33 (m, 1H), 7.30-7.19 (m, 1H),3.40-3.31 (m, 3H), 1.37-1.30 (m, 9H). LCMS Method 4—Tr=2.14 min (ES+)(M+H)+ 274.

[Intermediate 12]—tert-Butyl N-[methyl(oxo)[2-(piperazin-1-yl)phenyl]-λ⁶-sulfanylidene]carbamate

tert-Butyl N-[(2-fluorophenyl)(methyl)oxo-λ⁶-sulfanylidene]carbamate[Intermediate 11] (6.5 g, 19.0 mmol) and piperazine (6.55 g, 76.1 mmol)were heated neat in a pressure tube at 110° C. for 18 h. The reactionmixture was cooled to rt and then dissolved in water (20 ml) and EtOAc(20 ml). The phases were separated and the aqueous phase was extractedwith EtOAc (3×20 ml). The combined organics were washed with brine (2×30ml) and then concentrated in vacuo to afford a viscous pale brown oil.The crude material was purified by flash column chromatography elutingfirst with EtOAc in heptane (0% with gradient towards 100%), thenmethanol in EtOAc, (0% with gradient towards 100%). The fractionscontaining product were combined and concentrated in vacuo to afford apale yellow viscous oil. DCM (5 ml) was added and the mixture wassonication. The solid that formed was removed via filtration and thefiltrate was concentrated in vacuo to give a clear pale yellow viscousoil. The material was dried in a vacuum oven to afford the titlecompound as a pale yellow glass (4.5 g, 68%). ¹H NMR (500 MHz,Chloroform-d) δ 8.14 (dd, J=8.0, 1.5 Hz, 1H), 7.64 (td, J=7.9, 1.5 Hz,1H), 7.45 (dd, J=8.0, 0.9 Hz, 1H), 7.42-7.37 (m, 1H), 3.56 (s, 3H),3.16-3.07 (m, 4H), 3.07-3.01 (m, 2H), 2.92-2.81 (m, 2H), 1.39 (s, 9H).LCMS Method 2—Tr=0.77 min (ES+) (M+H)+ 340.

[Intermediate 13]—tert-ButylN-({2-[4-(5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoyl)piperazin-1-yl]phenyl}(methyl)oxo-λ-sulfanylidene)carbamate

The title compound was synthesized from5-{[1-(2-cyanophenyl)piperidin-4-yl](methyl)amino}-2,4-dimethylbenzoicacid [Intermediate 1] (259 mg, 0.742 mmol) and tert-butylN-[(2-fluorophenyl)(methyl)oxo-λ⁶-sulfanylidene]carbamate [Intermediate12] (350 mg, 0.928 mmol) using the method described above for Example 1to afford the title compound as an off-white glass (440 mg, 71%). ¹H NMR(250 MHz, Chloroform-d) δ 8.15 (d, J=8.0 Hz, 1H), 7.75-7.60 (m, 1H),7.59-7.37 (m, 4H), 7.11-6.97 (m, 2H), 6.92 (s, 1H), 6.48 (s, 1H),3.69-2.33 (m, 16H), 2.32-2.06 (m, 8H), 1.89-1.63 (m, 2H), 1.38 (s, 9H).LCMS Method 4—Tr=1.94 min (ES+) (M+H)+ 671.

[Intermediate 14]—2-(Piperazin-1-yl)benzamide

Prepared via the method of Lagu et al. Journal of Medicinal Chemistry(1999) 42, 23, 4794-4803.

[Intermediate 15]—Methyl 5-hydroxy-2-methylbenzoate

To a solution of 5-hydroxy-2-methylbenzoic acid (750 mg, 4.93 mmol) inmethanol (20 ml) at rt was dropwise added acetyl chloride (1.94 g, 24.65mmol) and the reaction was heated at 80° C. for 2 h. The reactionmixture was cooled to rt and then concentrated in vacuo to afford thetitle compound as a brown solid (750 mg, 91%). ¹H NMR (250 MHz,Chloroform-d) δ 7.41 (d, J=2.8 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.91(dd, J=8.3, 2.8 Hz, 1H), 3.88 (s, 3H), 2.50 (s, 3H). LCMS Method2—Tr=0.94 min (ES+) (M+H)+ 166.9.

[Intermediate 16]—tert-Butyl4-[2-(methylsulfanyl)pyridin-3-yl]piperazine-1-carboxylate

tert-Butyl piperazine-1-carboxylate (456 mg, 2.45 mmol),3-bromo-2-(methylsulfanyl)pyridine (500 mg, 2.45 mmol) and cesiumcarbonate (1.20 g, 3.68 mmol) were suspended in anhydrous toluene (5ml). Nitrogen was bubbled through the reaction for 20 min. Pd₂(dba)₃ (22mg, 0.024 mmol) and (+)-BINAP (38 mg, 0.061) were added and the reactionmixture bubbled with nitrogen for 10 min; the pressure tube was sealedand heated at 110° C. overnight. The reaction mixture was cooled to rtand filtered through a sintered glass funnel, the solid was extractedwith EtOAc (˜10 ml). The filtrate was concentrated in vacuo to afford abrown oily liquid. The crude material was purified by flash columnchromatography eluting with EtOAc in heptane (0% with gradient towards100%). The product-containing fractions were combined and concentratedin vacuo to afford to the title compound as a viscous brownish-yellowoil (660 mg, 84%). ¹H NMR (500 MHz, Chloroform-d) δ 8.09 (dd, J=4.8, 1.6Hz, 1H), 7.39 (dd, J=7.7, 1.4 Hz, 1H), 6.96 (dd, J=7.7, 4.8 Hz, 1H),3.63-3.56 (m, 4H), 3.22-3.16 (m, 4H), 2.43 (s, 3H), 1.48 (s, 9H). LCMSMethod 4—Tr=1.82 min (ES+) (M+H)+ 310.

[Intermediate 17]—tert-Butyl4-(2-methanesulfinylpyridin-3-yl)piperazine-1-carboxylate

tert-Butyl 4-[2-(methylsulfanyl)pyridin-3-yl]piperazine-1-carboxylate[Intermediate 16] (650 mg, 2.10 mmol) was suspended in THF (6 ml) at 0°C. then mCPBA (399 mg, 2.31 mmol) was added portionwise and the reactionwas stirred at rt overnight. The reaction mixture was diluted with aq.sodium bisulfite (10%, 20 ml) and DCM (30 ml) and the phases separated.The aqueous layer was extracted with DCM (3×20 ml). The organics werecombined and washed with brine (30 ml), dried (MgSO₄) and filtered. Thefiltrate was concentrated in vacuo and the residue was purified by flashcolumn chromatography eluting with EtOAc in heptane (0% with gradienttowards 100%). The fractions containing product were combined andconcentrated in vacuo to afford the title compound as a yellow oil (360mg, 44%). ¹H NMR (250 MHz, Chloroform-d) δ 8.39 (dd, J=4.8, 1.8 Hz, 1H),8.24 (dd, J=7.7, 1.8 Hz, 1H), 7.20 (dd, J=7.7, 4.9 Hz, 1H), 3.67-3.34(m, 6H), 3.20-3.02 (m, 2H), 2.81 (s, 3H), 1.48 (s, 9H). LCMS Method4—Tr=1.51 min (ES+) (M+H)+ 326.

[Intermediate 18]—tert-butyl4-{2-[methyl(oxo)[(trifluoroacetyl)imino]-λ-sulfanyl]pyridin-3-yl}piperazine-1-carboxylate

To a suspension of tert-butyl4-(2-methanesulfinylpyridin-3-yl)piperazine-1-carboxylate [Intermediate17](1.60 g, 4.92 mmol), trifluoroacetamide (1.11 g, 9.83 mmol),magnesium oxide (793 mg, 19.67 mmol) and rhodium(II)acetate (65 mg,0.147 mmol) in DCM (10 mL) was added portionwisebis(acetyloxy)(phenyl)-lambda˜3˜-iodane (3.17 g, 9.83 mmol) and thereaction mixture stirred at rt overnight. The solids were filtered offand extracted with DCM (˜10 mL). The filtrate was concentrated in vacuoand the crude product obtained. The crude product was purified by flashcolumn chromatography eluting with ethyl acetate in heptane (0% withgradient towards 100%). The product rich fractions were combined andconcentrated in vacuo to afford to the title compound as a yellow oil(400 mg, 15%). ¹H NMR (500 MHz, Chloroform-d) δ 8.41 (dd, J=4.5, 1.4 Hz,1H), 7.72 (dd, J=8.2, 1.4 Hz, 1H), 7.59 (dd, J=8.2, 4.4 Hz, 1H), 3.73(s, 3H), 3.66-3.61 (m, 4H), 3.12-3.07 (m, 4H), 1.48 (s, 9H). LCMS Method4—Tr=1.81 min (ES+) (M+H)+ 437.

[Intermediate 19] 1-(2-chloropyridin-3-yl)piperazine

A suspension of tert-butyl4-{2-[methyl(oxo)[(trifluoroacetyl)imino]-λ-sulfanyl]pyridin-3-yl}piperazine-1-carboxylate[Intermediate 18] (400 mg, 0.928 mmol) in DCM (10 mL) was added 4M HClin dioxane (5 mL) and the reaction mixture stirred at rt for 1 h. After1 h, the reaction mixture was concentrated in vacuo and the crudematerial was dissolved in DCM (1 mL) and loaded onto an SCX-2 column.DCM/MeOH (50:50, 30 mL) was washed through the column first and thisfraction discarded. Secondly, 7N NH₃ in MeOH (30 mL) was eluted throughthe column and this fraction concentrated in vacuo to afford the titlecompound as a yellow viscous oil (190 mg, 42%).

[Intermediate 20]2-{4-[(tert-butoxy)carbonyl]piperazin-1-yl}-5-fluorobenzoic acid

5-fluoro-2-(piperazin-1-yl)benzoic acid (500 mg, 2.23 mmol),di-tert-butyl dicarbonate (535 mg, 2.45 mmol) and sodium hydrogencarbonate (562 mg, 6.69 mmol) were suspended in THF (8 ml) and stirredat rt for 1 h. The mixture was concentrated under reduced pressure. Theresidue obtained was partitioned between DCM (30 ml) and water (30 ml).The organic layer was separated and the aqueous phase extracted with DCM(2×30 ml). The organics were combined, washed with brine (30 ml) andconcentrated in vacuo to yield a yellow oil. The oil was then purifiedby flash column chromatography eluting with a gradient from 0-100% EtOAcin heptane followed by 0-100% MeOH in EtOAc. The product containingfractions were combined and concentrated in vacuo to afford the titlecompound as a white solid (269 mg, 37%). ¹H NMR (250 MHz, DMSO-d6) δ7.76-7.62 (m, 2H), 7.50 (td, J=8.4, 3.2 Hz, 1H), 3.56-3.47 (m, 4H),3.06-2.97 (m, 4H), 1.43 (s, 9H). LCMS method 1—Tr=1.12 min (ES+) (M+H)+269.0.

[Intermediate 21]—tert-Butyl4-[4-fluoro-2-(methylcarbamoyl)phenyl]piperazine-1-carboxylate

2-{4-[(tert-Butoxy)carbonyl]piperazin-1-yl}-5-fluorobenzoic acid[Intermediate 20] (269 mg, 0.83 mmol) and DIPEA (520.05 μl, 2.99 mmol)were dissolved in DCM (8 ml) and placed under nitrogen atmosphere. Thereaction mixture was cooled 0° C. and thionyl chloride (73 μl, 1 mmol)was added. The mixture was stirred was warmed to rt and stirred for 1 h.The reaction mixture was cooled to 0° C. and methylamine hydrochloride(115 mg, 1.7 mmol) was added. The reaction was warmed to rt and stirredfor 1 h. The mixture was concentrated under reduced pressure. Theresultant residue was partitioned between DCM (20 ml) and water (20 ml).The aqueous phase was extracted with DCM (2×20 ml). The organic layerswere combined, washed with aq. 5 mM. aq. NaOH (30 ml) and concentratedin vacuo to yield a brown oil. The oil was purified flash columnchromatography eluting with gradient from 0-100% EtOAc in heptanefollowed by 0-100% MeOH in EtOAc. The product containing fractions werecombined and concentrated in vacuo to afford the title compound as abrown oil (273 mg, 52%). ¹H NMR (250 MHz, Chloroform-d) δ 9.69 (s, 1H),7.96-7.85 (m, 1H), 7.21-7.04 (m, 2H), 3.64-3.54 (m, 4H), 3.01 (dd,J=4.9, 0.7 Hz, 3H), 2.96-2.86 (m, 4H), 1.49 (d, J=0.7 Hz, 9H). LCMSMethod 1—Tr=1.21 min (ES+) (M+H)+ 338.0.

[Intermediate 22]—5-Fluoro-N-methyl-2-(piperazin-1-yl)benzamidedihydrochloride

tert-Butyl4-[4-fluoro-2-(methylcarbamoyl)phenyl]piperazine-1-carboxylate[Intermediate 21] (273 mg, 0.81 mmol) was suspended in 4M HCl in Dioxane(4 ml) and stirred at rt for 2 h. The reaction mixture was concentratedunder in vacuo to afford the title compound as a beige solid (259 mg,99%). ¹H NMR (250 MHz, Methanol-d4) δ 7.41 (dd, J=9.0, 3.0 Hz, 1H),7.37-7.17 (m, 2H), 3.40 (dd, J=6.4, 3.6 Hz, 4H), 3.25 (dd, J=6.4, 3.6Hz, 4H), 2.96 (s, 3H). LCMS Method 4—Tr=1.38 min (ES+) (M+H)+ 238.1.

[Intermediate 23]—tert-Butyl4-[2-(methylcarbamoyl)phenyl]piperazine-1-carboxylate

2-{4-[(tert-Butoxy)carbonyl]piperazin-1-yl}benzoic acid (626 mg, 1.98mmol) and DIPEA (1.2 ml, 7.14 mmol) were suspended in DCM (10 ml). Asolution of thionyl chloride (173 μl, 2.38 mmol) in DCM (5 ml) was thenadded dropwise to the stirred reaction mixture at 0° C. The reaction waswarmed to rt and stirred for 1 h. The reaction mixture was cooled to 0°C. and methylamine hydrochloride (121 mg, 1.79 mmol) was added. Thereaction mixture was warmed to rt and stirred for 16 h. The reactionmixture was concentrated in vacuo to yield an oil. The oil waspartitioned between DCM (30 ml) and aq. NaHCO₃(30 ml). The aqueous phaseextracted with DCM (2×30 ml). The organics layers were combined andwashed with aq. 0.1M NaOH (2×50 ml), dried over MgSO₄ and concentratedin vacuo to afford the title compound as a brown solid (286 mg, 55%). ¹HNMR (250 MHz, Chloroform-d) δ 9.32 (s, 1H), 8.14 (dd, J=7.8, 1.7 Hz,1H), 7.42 (td, J=7.8, 1.7 Hz, 1H), 7.25-7.17 (m, 1H), 7.13 (d, J=8.0 Hz,1H), 3.64-3.54 (m, 4H), 3.00 (d, J=4.9 Hz, 3H), 2.98-2.90 (m, 4H), 1.49(s, 9H). LCMS Method 1—Tr=1.16 min (ES+) (M+H)+ 320.0.

[Intermediate 24]—N-Methyl-2-(piperazin-1-yl)benzamide di-hydrochloride

tert-Butyl 4-[2-(methylcarbamoyl)phenyl]piperazine-1-carboxylate[Intermediate 23] (143 mg, 0.45 mmol) was suspended in 4M HCl in Dioxane(2 ml) and stirred at rt for 2 h. The reaction mixture was concentratedin vacuo to afford the title compound as a beige solid (124 mg, 93%). ¹HNMR (250 MHz, Methanol-d4) δ 7.77 (dd, J=7.7, 1.5 Hz, 1H), 7.65-7.56 (m,1H), 7.47 (dd, J=8.2, 1.0 Hz, 1H), 7.36 (td, J=7.6, 1.2 Hz, 1H), 3.50(s, 8H), 2.99 (s, 3H). LCMS Method 10—Tr=0.38 min (ES+) (M+H)+ 220.1.

[Intermediate 25]—(1-Phenylpiperazin-2-yl)methanol

1-Phenylpiperazine-2-carboxylic acid dihydrochloride (250 mg, 0.9 mmol)was suspended in anhydrous tetrahydrofuran (5 ml) under nitrogen. Thereaction was cooled to 0° C. and 4M lithium aluminum hydride in Et₂O(672 μl) was added slowly. The reaction was stirred at rt for 2 h. Thereaction was diluted with DCM (15 ml) and sat. aq. NH₄Cl (30 ml) wasadded dropwise to the stirring reaction mixture. The biphasic suspensionwas filtered, then the organics were separated and concentrated in vacuoto yield the title compound as a tan oil (179 mg, 100%). ¹H NMR (500MHz, DMSO-d6) δ 7.17 (ddt, J=9.7, 7.3, 2.0 Hz, 2H), 6.84 (d, J=8.0 Hz,2H), 6.67 (t, J=7.2 Hz, 1H), 3.74 (t, J=9.8 Hz, 1H), 3.21 (dt, J=6.4,4.3 Hz, 2H), 3.14 (d, J=12.0 Hz, 1H), 3.02 (dd, J=6.0, 4.0 Hz, 1H), 2.94(d, J=11.7 Hz, 1H), 2.82 (ddt, J=11.6, 7.8, 3.4 Hz, 2H), 2.74 (dd,J=11.7, 3.3 Hz, 1H), 2.66 (td, J=11.6, 3.5 Hz, 1H).

[Intermediate 26]—tert-Butyl4-(3-sulfamoylpyridin-2-yl)piperazine-1-carboxylate

2-Chloropyridine-3-sulfonamide (250 mg, 1.3 mmol), tert-butylpiperazine-1-carboxylate (290 mg, 1.56 mmol) and potassium carbonate(215 mg, 1.56 mmol) were suspended in DMF (5 ml). The mixture was thenheated via microwave irradiation at 130° C. for 3 h. The mixture wasconcentrated in vacuo the resultant residue was partitioned between DCM(20 ml) and water (20 ml). The aqueous phase was extracted with DCM(2×20 ml). The organic layers were combined and the solvents removedunder reduced pressure. The residue obtained was purified flash columnchromatography eluting with gradient from 0-100% EtOAc in heptanefollowed by 0-100% MeOH in EtOAc. The product containing fractions werecombined and concentrated in vacuo to give a clear oil. The oil waspurified flash column chromatography eluting with gradient from 0% MeOHto 10% MeOH in DCM. The product containing fractions were concentratedin vacuo to afford the title compound as a white solid (259 mg, 58%). ¹HNMR (250 MHz, DMSO-d6) δ 8.48 (dd, J=4.7, 1.8 Hz, 1H), 8.22 (dd, J=7.8,1.8 Hz, 1H), 7.34-7.21 (m, 3H), 3.57-3.44 (m, 4H), 3.23-3.10 (m, 4H),1.42 (s, 9H). LCMS Method 1—Tr=1.77 min (ES+) (M+H)+ 343.0.

[Intermediate 27]—2-(Piperazin-1-yl)pyridine-3-sulfonamide

tert-Butyl 4-(3-sulfamoylpyridin-2-yl)piperazine-1-carboxylate[Intermediate 26] (259 mg, 0.76 mmol) was suspended in 4M HCl in Dioxane(4 ml) and stirred at rt overnight. The reaction was concentrated invacuo and the residue was loaded onto a Biotage SCX-2 column (10 g) andwashed with 1:1 DCM/MeOH (40 ml). The product was then eluted with 7NNH₃ in MeOH (40 ml) and concentrated in vacuo to afford the titlecompound as a white solid (181 mg, 82%). ¹H NMR (250 MHz, Chloroform-d)δ 7.84 (s, 1H), 7.54 (dd, J=8.0, 1.6 Hz, 1H), 7.50-7.40 (m, 1H), 7.11(s, 1H), 7.01-6.92 (m, 2H), 3.67-3.53 (m, 2H), 2.99-2.87 (m, 1H),2.87-2.73 (m, 2H), 2.70 (s, 3H), 2.59 (s, 3H), 2.34 (s, 3H), 1.98-1.82(m, 4H). LCMS Method 4—Tr=1.03 min (ES+) (M+H)+ 243.1.

[Intermediate 28]—Methyl2,4-dimethyl-5-[(1-phenylpiperidin-4-yl)amino]benzoate

Methyl 5-amino-2,4-dimethylbenzoate (300 mg, 1.67 mmol) and1-phenylpiperidin-4-one (324 mg, 1.76 mmol) were suspended in DCM (10ml) and stirred at rt for 1 h. NaBH(OAc)₃ (887 mg, 4.18 mmol) was addedand the reaction was stirred for 1 hr. 1-phenylpiperidin-4-one (50 mg,0.27 mmol) was added and the reaction was stirred for 17 h. The mixturewas diluted with DCM (20 ml) and water (20 ml). The aqueous phaseextracted with DCM (2×20 ml). The organic layers were combined andreduced in vacuo. The residue obtained was then purified flash columnchromatography eluting with gradient from 0-100% EtOAc in heptanefollowed by 0-100% MeOH in EtOAc. The product containing fractions werecombined and concentrated in vacuo to afford the title compound as awhite solid (518 mg, 91%). ¹H NMR (250 MHz, DMSO-d6) δ 7.20 (dd, J=8.7,7.2 Hz, 2H), 7.08 (s, 1H), 6.96 (s, 1H), 6.93 (s, 2H), 6.74 (t, J=7.2Hz, 1H), 4.51 (d, J=8.1 Hz, 1H), 3.79 (s, 3H), 3.76-3.65 (m, 2H),3.53-3.36 (m, 1H), 2.94-2.77 (m, 2H), 2.34 (s, 3H), 2.10 (s, 3H),2.03-1.89 (m, 2H), 1.58 (d, J=11.7 Hz, 2H). LCMS Method 1—Tr=1.22 min(ES+) (M+H)+ 339.1.

[Intermediate 29]—2,4-Dimethyl-5-[(1-phenylpiperidin-4-yl)amino]benzoicacid

To a stirred suspension of methyl2,4-dimethyl-5-[(1-phenylpiperidin-4-yl)amino]benzoate [Intermediate 28](518 mg, 1.53 mmol) in (4:1) Methanol/Water (5 ml) was added aq. 2M LiOH(3.0 ml). The reaction mixture was then heated at 65° C. for 3 h. Themixture was concentrated in vacuo, then partitioned between DCM (20 ml)and water (20 ml). The aqueous phase was extracted with DCM (3×20 ml).The organic layers were combined and reduced in vacuo to afford thetitle compound as a pink solid (490 mg, 99%). ¹H NMR (250 MHz,Chloroform-d) δ 7.37 (s, 1H), 7.31 (s, 1H), 7.25 (s, 1H), 7.06-6.94 (m,3H), 6.87 (t, J=7.3 Hz, 1H), 3.74-3.51 (m, 3H), 3.08-2.90 (m, 2H), 2.53(s, 3H), 2.23 (d, J=10.1 Hz, 2H), 2.16 (s, 3H), 1.75-1.56 (m, 2H). LCMSMethod 1—Tr=1.08 min (ES+) (M+H)+ 325.0.

[Intermediate 30]—2-(Piperazin-1-yl)pyridine-3-carboxamide

2-(piperazin-1-yl)pyridine-3-carbonitrile (250 mg, 1.33 mmol) wassuspended in conc. sulfuric acid(5 ml) and stirred at 100° C. for 19 h.The reaction mixture was then diluted with water (30 ml), basified to pH14 with aq. sat. NaOH and extracted with chloroform/isopropanol (9:1,3×30 ml). The combined organics were concentrated under reduced pressureto afford the title compound as a tan solid (128 mg, 47%). ¹H NMR (500MHz, Chloroform-d) δ 8.55 (s, 1H), 8.40 (dd, J=4.8, 2.0 Hz, 1H), 8.31(dd, J=7.6, 2.0 Hz, 1H), 7.09 (dd, J=7.6, 4.8 Hz, 1H), 5.90 (s, 1H),3.22-3.16 (m, 4H), 3.07-3.01 (m, 4H). LCMS Method 4—Tr=1.03 min (ES+)(M+H)+207.4.

[Intermediate 31]—5-Iodo-2,4-dimethylbenzoic Acid

2,4-Dimethylbenzoic acid (25 g, 166 mmol), sodium periodate (17.8 g, 83mmol) and Iodine (46.5 g, 183 mmol) were suspended in glacial aceticacid (188 ml). Sulfuric acid (1.3 ml, 25 mmol) was added and thereaction was heated at 110° C. for 6 h. The reaction mixture was addedslowly to water (1.2 L) and the residuals washed in with a further 300ml water. Aq. sat. Na₂S₂O₃ (1 L) was added to the aqueous suspension.The suspension was agitated for 20 mins. The suspension was filtered togive a white solid. The solid was triturated with EtOAc (250 ml×2), andfiltered to afford the title compound as a pale solid (25.6 g, 56%). ¹HNMR (500 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.27 (s, 1H), 2.44 (s, 3H), 2.36(s, 3H). LCMS Method 2—Tr=1.14 min.

[Intermediate 32]—methyl 5-iodo-2,4-dimethylbenzoate

5-Iodo-2,4-dimethylbenzoic acid [Intermediate 31] (10 g, 36 mmol) wassuspended in methanol (100 ml) then sulfuric acid (1.9 ml, 36.2 mmol)was added and the reaction was stirred at 80° C. for 2 h. The reactionwas concentrated in vacuo then the residue was taken up in DCM (50 ml).Aq. sat. NaHCO₃ (50 ml) was added followed by water (25 ml) and thereaction was agitated for 10 mins. The biphasic suspension was filteredand the organic layer was separated, dried Na₂SO₄, filtered andconcentrated in vacuo to afford the title compound as a pale yellowcrystallized solid (4.1 g, 39%). ¹H NMR (500 MHz, DMSO-d6) δ 8.19 (s,1H), 7.31 (s, 1H), 3.81 (s, 3H), 2.43 (s, 3H), 2.37 (s, 3H). LCMS Method2—Tr=1.35 min (ES+) (M+H)+ 290.8.

[Intermediate33]—[4-(2,4-Dimethyl-5-nitrobenzoyl)-1-phenylpiperazin-2-yl]methanol

2,4-Dimethyl-5-nitrobenzoic acid (120 mg, 0.61 mmol), DIPEA (321 μl,1.84 mmol) and HATU (280 mg, 0.74 mmol) were suspended in DMF (2 ml) andstirred at rt for 20 min. (1-Phenylpiperazin-2-yl)methanol [Intermediate25] (166 mg, 0.61 mmol) in DMF (2 ml) was then added and the mixture wasstirred for 72 h. The reaction mixture was concentrated in vacuo. Theresultant residue was partitioned between DCM (20 ml) and water (20 ml).The aqueous phase was extracted with DCM (20 ml). The organic layerswere combined and reduced in vacuo to give an orange oil. The oil waspurified by flash column chromatography eluting with gradient from0-100% EtOAc in heptane followed by 0-100% MeOH in EtOAc. The productcontaining fractions were reduced in vacuo to give a yellow oil. The oilwas further purified by flash column chromatography eluting withgradient from 0% to 50% EtOAc in heptane. The product containingfractions were combined and concentrated in vacuo to afford the titlecompound as a yellow solid (162 mg, 71%). ¹H NMR (250 MHz, Chloroform-d)δ 7.95-7.86 (m, 1H), 7.34-7.26 (m, 2H), 7.25-7.19 (m, 1H), 6.91 (d,J=7.8 Hz, 3H), 4.74 (d, J=13.3 Hz, 1H), 3.76-3.54 (m, 3H), 3.53-3.34 (m,3H), 3.32-2.91 (m, 2H), 2.66-2.58 (m, 3H), 2.45-2.35 (m, 3H). LCMSMethod 10—Tr=1.18 min (ES+) (M+H)+ 370.1.

[Intermediate34]—[4-(5-Amino-2,4-dimethylbenzoyl)-1-phenylpiperazin-2-yl]methanol

To a suspension of[4-(2,4-dimethyl-5-nitrobenzoyl)-1-phenylpiperazin-2-yl]methanol[Intermediate 33] (162 mg, 0.44 mmol) in ethanol/water (5:1, 6 ml) wasadded iron powder (86 mg, 1.53 mmol) and ammonium chloride (26 mg, 0.48mmol). The mixture was heated at 80° C. for 16 h. The reaction mixturewas cooled to rt, then filtered through Celite. The filtrate wasconcentrated under reduced pressure to afford the title compound as anoff-white solid (143 mg, 93%). ¹H NMR (250 MHz, DMSO-d6) δ 7.26-7.14 (m,2H), 6.91 (s, 1H), 6.88 (s, 1H), 6.84-6.68 (m, 2H), 6.42 (d, J=6.2 Hz,1H), 4.91-4.46 (m, 4H), 4.17-3.38 (m, 4H), 3.25-3.02 (m, 2H), 3.01-2.76(m, 1H), 2.08-1.99 (m, 6H). LCMS Method 1—Tr=0.95 min (ES+) (M+H)+340.2.

[Intermediate 35]—tert-Butyl3-(2-methoxy-2-oxoethyl)-4-phenylpiperazine-1-carboxylate

tert-Butyl 3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (100 mg,0.39 mmol), bromobenzene (41 μl, 0.39 mmol), DavePhos (15 mg, 0.04mmol), Pd₂(dba)₃ (18 mg, 0.02 mmol) and cesium carbonate (252 mg, 0.77mmol) were suspended in de-gassed anhydrous toluene (5 ml) and themixture was stirred at 100° C. for 22 h. The reaction mixture was cooledto rt, then filtered through Celite, washing with EtOAc (20 ml). Thefiltrate was concentrated in vacuo to give a brown oil. The oil waspurified by flash column chromatography eluting with gradient from0-100% EtOAc in heptane followed by 0-100% MeOH in EtOAc. The productcontaining fractions were combined and concentrated in vacuo to affordthe title compound as a yellow oil (59 mg, 46%). ¹H NMR (250 MHz,Chloroform-d) δ 7.32-7.26 (m, 1H), 7.26-7.22 (m, 1H), 6.87 (dd, J=15.0,7.7 Hz, 3H), 4.35-4.11 (m, 2H), 4.09-3.99 (m, 1H), 3.60 (s, 3H),3.35-3.18 (m, 2H), 3.13-2.94 (m, 2H), 2.67-2.51 (m, 1H), 2.41-2.25 (m,1H), 1.47 (s, 9H). LCMS Method 4—Tr=1.86 min (ES+) (M+H)+ 335.3.

[Intermediate 36]—2-(1-Phenylpiperazin-2-yl)ethan-1-ol

tert-Butyl 3-(2-methoxy-2-oxoethyl)-4-phenylpiperazine-1-carboxylate[Intermediate 35] (89 mg, 0.27 mmol) was suspended in anhydrous THF (5ml) and stirred under nitrogen at 0° C. 2.4 M Lithium aluminum hydridein THF (0.33 ml) was added dropwise to the reaction mixture and stirredfor 10 min at 0° C., then warmed to rt and stirred 3 h. The reactionmixture was diluted with DCM (3 ml) and cooled to 0° C. sat. aq. NH₄Cl(10 ml) was added and the mixture was stirred for 10 min, then warmed tort. The reaction mixture was partitioned between DCM (10 ml) and water(10 ml). The aqueous phase was extracted with DCM (20 ml) and theorganic phases were combined and reduced in vacuo to afford the titlecompound as a yellow oil (81 mg, 27%). LCMS Method 4—Tr=1.68 min (ES+)(M+H)+ 307.2.

[Intermediate 37]—2-(1-Phenylpiperazin-2-yl)ethan-1-ol dihydrochloride

tert-Butyl 3-(2-hydroxyethyl)-4-phenylpiperazine-1-carboxylate[Intermediate 36] (81 mg, 0.13 mmol) was suspended in 4M HCl in Dioxane(0.63 ml) and stirred at rt for 16 h. The reaction mixture wasconcentrated in vacuo to afford the title compound as a brown solid (105mg, 100%). LCMS Method 4—Tr=1.36 min (ES+) (M+H)+ 207.3.

[Intermediate38]—2-[4-(5-Amino-2,4-dimethylbenzoyl)piperazin-1-yl]benzonitrile

The title compound was synthesized from 2-(piperazin-1-yl)benzonitrile(403 mg, 2.15 mmol) and 2,4-dimethyl-5-nitrobenzoic acid (400 mg, 2.05mmol) using the method described above for Intermediate 33 & 34 toafford the title compound as a white foamy solid (723 mg, 100%). ¹H NMR(250 MHz, Chloroform-d) δ 7.58 (dd, J=7.7, 1.6 Hz, 1H), 7.51 (td, J=8.2,1.6 Hz, 1H), 7.12-6.97 (m, 2H), 6.90 (s, 1H), 6.51 (s, 1H), 6.51 (s,1H), 4.07-3.33 (m, 6H), 3.24 (d, J=4.7 Hz, 2H), 3.09 (d, J=4.6 Hz, 2H),2.18 (s, 3H), 2.15 (s, 3H). LCMS Method 1—Tr=1.08 min (ES+) (M+H)+334.8.

[Intermediate 39]—1-Phenylazepan-4-one

Azepan-4-one hydrochloride (250 mg, 1.67 mmol), phenylboronic acid (407mg, 3.34 mmol), copper (II) acetate (303 mg, 1.67 mmol) and pyridine(405μl, 5.01 mmol) were suspended in anhydrous DCM (10 ml). 4A molecularsieves (450 mg) were added and the mixture was stirred at rt with airbubbled through the mixture for 1 hr. The reaction was stirred for 16 hat rt, then 9 h at 40° C. The mixture was filtered through Celite andthe filtrate was partitioned between water (30 ml) and DCM (20 ml). Theaqueous phase was extracted with DCM (2×20 ml). The organics werecombined and concentrated in vacuo to give a brown oil. The oil waspurified by flash column chromatography eluting with gradient from0-100% EtOAc in heptane. The product containing fractions were combinedand concentrated in vacuo to afford the title compound as a white solid(98 mg, 31%). ¹H NMR (250 MHz, Chloroform-d) δ 7.26-7.17 (m, 2H),6.77-6.67 (m, 3H), 3.81-3.71 (m, 2H), 3.69-3.59 (m, 2H), 2.79-2.70 (m,2H), 2.68-2.60 (m, 2H), 1.95-1.83 (m, 2H). LCMS Method 4—Tr=1.64 min(ES+) (M+H)+ 190.2.

[Intermediate 40]—[2-(Piperazin-1-yl)phenyl]methanol

2-(Piperazin-1-yl)benzoic acid (80 mg, 0.39 mmol) was suspended inanhydrous THF (5 ml) under nitrogen atmosphere at 0° C. 2.4M Lithiumaluminum hydride in THF (485 μl) was added dropwise to the reactionmixture. The reaction mixture was warmer to rt and stirred for 3 h. Thereaction was cooled to 0° C., diluted with DCM (5 ml) and quenched withsat. aq. NH₄Cl (10 ml). The biphasic solution was stirred for 5 min andwarmed to rt. 2M aq. NaOH (20 ml) was added. The organic layer wasseparated and the aqueous phase extracted with DCM (2×20 ml). Thecombined organics were concentrated in vacuo to afford the titlecompound as a yellow oil (74 mg, 87%). ¹H NMR (250 MHz, Chloroform-d) δ7.32-7.26 (m, 1H), 7.25-7.07 (m, 3H), 4.81 (s, 2H), 3.06 (dd, J=6.1, 2.8Hz, 4H), 2.96 (dd, J=6.3, 2.9 Hz, 4H). LCMS Method 4—Tr=1.30 min (ES+)(M+H)+ 193.3.

[Intermediate 41]—tert-butyl3-(hydroxymethyl)-4-(pyrazin-2-yl)piperazine-1-carboxylate

2-Chloropyrazine (250 mg, 2.18 mmol), tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate (495 mg, 2.29 mmol), (+/−)BINAP (14 mg, 0.02 mmol), Pd(OAc)₂ (25 mg, 0.11 mmol) and cesiumcarbonate (1.4 g, 4.4 mmol) were suspended in anhydrous de-gassedtoluene (10 ml). The mixture was de-gassed with nitrogen for 5 minutesthen sealed under a nitrogen atmosphere and stirred at 100° C. for 18 h.The reaction mixture was cooled to rt and filtered through Celite,washing with EtOAc. The filtrate was concentrated in vacuo. Theresultant orange oil was purified by flash column chromatography elutingwith gradient from 0-100% EtOAc in heptane followed by 0-100% MeOH inEtOAc. The product containing fractions were combined and concentratedin vacuo to give a yellow oil. The oil was purified by preparative HPLC[UV-Directed High pH prep method]. The fractions containing product werecombined and concentrated in vacuo to yield the title compound as aclear gel (170 mg, 25%). ¹H NMR (250 MHz, Chloroform-d) δ 8.17-8.12 (m,1H), 8.06-7.99 (m, 1H), 7.86 (d, J=2.6 Hz, 1H), 4.54-4.42 (m, 1H),4.35-3.90 (m, 3H), 3.78-3.59 (m, 2H), 3.18 (s, 4H), 1.49 (s, 9H). LCMSMethod 1—Tr=1.03 min (ES+) (M+H)+ 295.3

[Intermediate 42]—[1-(Pyrazin-2-yl)piperazin-2-yl]methanoldihydrochloride

tert-Butyl 3-(hydroxymethyl)-4-(pyrazin-2-yl)piperazine-1-carboxylate[Intermediate 41] (170 mg, 0.54 mmol) was suspended in 4M HCl in Dioxane(3 ml) and stirred at rt for 1 h. The reaction mixture was concentratedin vacuo to afford the title compound as a yellow solid (159 mg, 94%).¹H NMR (250 MHz, DMSO-d6) δ 9.90-9.63 (m, 1H), 9.29-8.94 (m, 1H), 8.38(d, J=1.4 Hz, 1H), 8.16 (dd, J=2.7, 1.4 Hz, 1H), 7.88 (d, J=2.7 Hz, 1H),4.64-4.52 (m, 2H), 4.46-4.31 (m, 1H), 3.86-3.63 (m, 2H), 3.52-2.88 (m,6H). LCMS Method 4—Tr=1.10 min (ES+) (M+H)+ 195.2.

[Intermediate 43]—5-Hydroxy-2,4-dimethylbenzoic Acid

Prepared by the method of Adediran Cabaret et al. Journal of OrganicChemistry (1999) 64, 3, 713-720.

To a stirred solution of methyl 5-amino-2,4-dimethylbenzoate (250 mg,1.39 mmol) in 20% sulfuric acid (aq) (10 ml) at 0° C. was added asolution of NaNO₂ (115 mg, 1.67 mmol) in water (5 ml). Conc sulfuricacid (8 ml) was then added. The resultant solution was then added toboiling 50% aq sulfuric acid (30 ml) at 100° C. The reaction mixture wasstirred for 10 min then poured over ice and extracted with EtOAc. Theorganics were concentrated in vacuo then purified via flash columnchromatography using 9:1 DCM/MeOH. The fractions containing product werecombined and the solvent removed in vacuo to yield the title compound(151 mg, 65%). ¹H NMR (250 MHz, Methanol-d4) δ 7.36 (s, 1H), 6.98 (s,1H), 2.46 (s, 3H), 2.21 (s, 3H).

[Intermediate44]—2-[4-(5-Hydroxy-2,4-dimethylbenzoyl)piperazin-1-yl]benzonitrile

5-Hydroxy-2,4-dimethylbenzoic acid [Intermediate 43] (151 mg, 0.91 mmol)and HATU (414 mg, 1.09 mmol) were suspended in DMF (5 ml) and stirred atrt for 20 min. 2-(Piperazin-1-yl)benzonitrile (187 mg, 1 mmol) and DIPEA(475 μl, 2.7 mmol) were then added and the reaction was stirred for 16h. The reaction was concentrated in vacuo. The residue was partitionedbetween DCM (20 ml) and water (20 ml) then the organics were separatedand the aqueous phase extracted with DCM (2×20 ml). The combinedorganics were concentrated in vacuo then the residue was purified viaflash column chromatography (gradient of 0-100% EtOAc in heptanefollowed by 0-100% MeOH in EtOAc). The fractions containing product werecombined and concentrated in vacuo to give a yellow solid. The solid wasthen loaded onto the UV Direct High pH preparative HPLC system. Thefractions containing product were collected and the solvents removed invacuo to yield the title compound as a yellow solid (56 mg, 18%). ¹H NMR(250 MHz, Chloroform-d) δ 7.59 (dd, J=7.7, 1.5 Hz, 1H), 7.56-7.47 (m,1H), 7.07 (t, J=7.2 Hz, 1H), 7.01 (s, 1H), 6.89 (s, 1H), 6.64-6.56 (m,2H), 4.02 (d, J=40.6 Hz, 2H), 3.48 (t, J=4.9 Hz, 2H), 3.32-3.17 (m, 2H),3.13-3.01 (m, 2H), 2.19 (s, 3H), 2.15 (s, 3H). LCMS Method 8—Tr=1.61 min(ES+) (M+H)+ 336.2.

Intermediate 45]-3-(4-Oxoazepan-1-yl)benzonitrile

Azepan-4-one hydrochloride (125 mg, 0.84 mmol), (3-cyanophenyl)boronicacid (24 mg, 1.67 mmol), copper(II) acetate (152 mg, 0.84 mmol),pyridine(202 μl, 2.51 mmol) and 4 Å molecular sieves (500 mg) weresuspended in anhydrous DCM (10 ml). The reaction mixture was stirred at40° C. for 18 h. The reaction mixture was cooled to rt and filteredthrough Celite. The filtrate was concentrated in vacuo to give a brownoil. The oil was purified by flash column chromatography eluting withgradient from 0-100% EtOAc in heptane followed by 0-100% MeOH in EtOAc.The product containing fractions were combined and reduced in vacuo toafford the title compound as a white solid (54 mg, 30%). ¹H NMR (250MHz, Chloroform-d) δ 7.32-7.23 (m, 1H), 6.99-6.92 (m, 1H), 6.91-6.83 (m,2H), 3.83-3.71 (m, 2H), 3.70-3.56 (m, 2H), 2.78-2.62 (m, 4H), 1.95-1.79(m, 2H). LCMS Method 4—Tr=1.58 min (ES+) (M+H)+ 215.2.

[Intermediate 46]—4-(4-Oxoazepan-1-yl)benzonitrile

The title compound was synthesized from (4-cyanophenyl)boronic acid (245mg, 1.67 mmol) using the method described above for Intermediate 45 toafford the title compound as a white solid (124 mg, 69%). ¹H NMR (250MHz, Chloroform-d) δ 7.46 (d, J=9.0 Hz, 2H), 6.66 (d, J=9.0 Hz, 2H),3.86-3.75 (m, 2H), 3.73-3.63 (m, 2H), 2.79-2.60 (m, 4H), 1.95-1.81 (m,2H). LCMS Method 4—Tr=1.55 min (ES+) (M+H)+ 215.

[Intermediate 47]—Methyl5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2-methylbenzoate

2-(4-Oxopiperidin-1-yl)benzonitrile [Intermediate 4] (200 mg, 1 mmol)was dissolved in dichloromethane (2.5 ml) then methyl3-amino-4-methylbenzoate (165 mg, 1 mmol) was added and the reaction wasstirred for 10 mins at ambient temperature. NaBH(OAc)₃ (423.39 mg, 2mmol) was then added and the reaction was stirred for a further 18 h.The reaction was partitioned between DCM (2.5 ml) and water (3 ml) thenthe reaction was stirred until no further gas evolution was observed.The organic layer was separated via filtration through a PTFE frittedtube and concentrated in vacuo. The residue obtained was purified viaflash column chromatography using a gradient of EtOAc (0% to 100%) inheptane. The fractions containing product were combined and concentratedin vacuo to afford the title compound as a clear gel (329 mg, 94%). LCMSMethod 2—Tr=1.24 min (ES+) (M+H⁺) 350.1.

[Intermediate48]—5-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-2-methylbenzoic acid

Methyl 5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2-methylbenzoate[Intermediate 47] (329 mg, 0.94 mmol) was dissolved in THF (5 ml) thenLiOH (2M aq, 941.52 μl) was added and the reaction was heated to 65° C.for 4 h. Further additions of 2M. aq. LiOH (2×1.0 ml) and the additionof MeOH (0.5 ml) were required to push the reaction to completion.Addition of an equivolume of 2M. aq, hydrochloric acid (2.94 ml),followed by the addition of DCM (15 ml) and water (10 ml) then thereaction was stirred for 5 minutes. The organics were separated viafiltration through a PTFE fritted tube and concentrated in vacuo toafford the title compound as a yellow powdery solid (254 mg, 72%). LCMSMethod 2—Tr=1.11 min (ES+) (M+H⁺) 336.1.

[Intermediate 49]—4-[(tert-Butoxy)carbonyl]-1-phenylpiperazine-2-carboxylic acid

1-Phenylpiperazine-2-carboxylic acid dihydrochloride (1.0 g, 3.58 mmol)was suspended in 1,4-dioxane (20 ml) then DIPEA (2.0 ml, 11.46 mmol) wasadded followed by the addition of di-tert-butyl dicarbonate (860 mg,3.94 mmol) and the reaction was stirred at rt for 2 h. The reaction wasconcentrated in vacuo then the residue was partitioned between DCM (20ml) and water (10 ml) then the organics were separated, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue obtained waspurified via flash column chromatography eluting with a gradients ofEtOAc (0% to 100%) in heptane followed by MeOH (0% to 100%) in EtOAc.Two peaks were noted with the desired mass; the relevant fractions forboth peaks were combined and concentrated in vacuo to give two crops ofthe title compound. The first crop was a white crystalline solid (513mg, 47%). LCMS Method 2—Tr=1.08 min (ES+) (M+H⁺) 307.1.

[Intermediate 50]—1-Phenylpiperazine-2-carboxamide Hydrochloride

4-[(tert-Butoxy)carbonyl]-1-phenylpiperazine-2-carboxylic acid (263 mg,0.86 mmol) and HATU (392 mg, 1.03 mmol) were suspended in 1,4-dioxane (5ml) then the reaction mixture was stirred for 1 h. Ammonium carbonate(99 mg, 1.03 mmol) was added and the reaction stirred at rt for 2 h.Further ammonium carbonate (99 mg, 1.03 mmol) was added then thereaction was stirred for 5 h. The reaction was then diluted with DCM (30ml) and water (15 ml) then the reaction was briefly stirred and theorganics were separated and concentrated in vacuo. The resulting residuewas taken up in 1,4-dioxane then 4M hydrochloric acid in 1,4-dioxane(2.5 ml) was added The reaction was agitated for 18 h. Further 4Mhydrochloric acid in 1,4-dioxane (2.5 ml) was added then the reactionmixture was agitated for a 6 h before concentration in vacuo to yieldthe title compound as a pale tan solid (192 mg, 93%). ¹H NMR (500 MHz,DMSO-d6) 9.41 (s, 1H), 8.44 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.25(dd, J=8.7, 7.3 Hz, 2H), 6.97 (d, J=8.0 Hz, 2H), 6.83 (t, J=7.3 Hz, 1H),4.56-4.50 (m, 1H), 3.58-3.50 (m, 3H), 3.23 (d, J=11.8 Hz, 2H), 3.06 (d,J=10.0 Hz, 1H).

[Intermediate 51]—Methyl3-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-4-methylbenzoate

Prepared analogously to the method of methyl5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2-methylbenzoate[Intermediate 47] from 2-(4-oxopiperidin-1-yl)benzonitrile [Intermediate4] (200 mg, 1 mmol) and methyl 5-amino-2-methylbenzoate (165 mg, 1 mmol)to yield the title compound as a clear gel (257 mg, 52%). LCMS Method2—Tr=1.29 min (ES+) (M+H⁺) 350.1.

[Intermediate52]—3-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-4-methylbenzoic acid

Prepared analogously to the method of5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2-methylbenzoic acid[Intermediate 48] from Methyl3-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-4-methylbenzoate (329 mg,0.94 mmol) to yield the title compound as a yellow powdery solid (218mg, 72%). LCMS Method 2—Tr=1.14 min (ES+) (M+H⁺) 336.1.

[Intermediate 53]—1-tert-Butyl 3-methyl(3R)-4-phenylpiperazine-1,3-dicarboxylate

Bromobenzene (125 mg, 0.8 mmol), 1-tert-butyl 3-methyl(3R)-piperazine-1,3-dicarboxylate (213.94 mg, 0.88 mmol),Pd₂(dba)₃.CHCl₃ (8.24 mg, 0.01 mmol), RuPhos (9.29 mg, 0.02 mmol) andCs₂CO₃ (324.24 mg, 1 mmol) were suspended in anhydrous toluene (2.5 ml).The sealed reaction was heated at 110° C. for 18 h. The reaction waspartitioned between DCM (5 ml) and water (5 ml) then the organics wereseparated and concentrated in vacuo. The residue was purified via flashcolumn chromatography using a gradient of 0% to 100% EtOAc in heptanethen 0% to 100% MeOH in EtOAc. Fractions containing product werecombined and concentrated in vacuo to yield the title compound as ayellow glassy solid (51 mg, 13%). LCMS Method 2—Tr=1.21 min (ES+) (M+H⁺)321.0.

[Intermediate 54] 2-[(2R)-1-phenylpiperazin-2-yl]propan-2-ol

1-tert-Butyl 3-methyl (3R)-4-phenylpiperazine-1,3-dicarboxylate (51 mg,0.16 mmol) was dissolved in anhydrous tetrahydrofuran (2.5 ml) then 3Mmethyl magnesium bromide in Et₂O (111 μl, 0.33 mmol) was added and thereaction was stirred at rt for 18 h. The reaction was partitionedbetween DCM (5 ml) and water (5 ml) then the organics were separated andconcentrated in vacuo. The residue was dissolved in DCM (2 ml) and thesolution was retreated with 3M methyl magnesium bromide in Et₂O (300 μl,0.9 mmol) and agitated for a further 3 h. The reaction was partitionedbetween DCM (5 ml) and water (5 ml) then the organics were separated andconcentrated in vacuo. The residue was dissolved in DCM (4 ml) and TFA(1 ml) was added and stirred at rt for 6 h. The reaction was dilutedwith further DCM (5 ml) and sat. aq. NaHCO₃ (5 ml), then agitated for 5minutes. The organics were separated and concentrated in vacuo to yieldthe crude title compound as a brown gel (28 mg, 44%). LCMS Method2—Tr=0.80 min (ES+) (M+H⁺) 221.15.

[Intermediate 55]—1-tert-Butyl 3-methyl(3S)-4-phenylpiperazine-1,3-dicarboxylate

Prepared analogously to the method of 1-tert-butyl 3-methyl(3R)-4-phenylpiperazine-1,3-dicarboxylate [Intermediate 53] fromI-tert-butyl 3-methyl (3S)-piperazine-1,3-dicarboxylate (214 mg, 0.88mmol) to yield the title compound as a yellow glass (45 mg, 16%). LCMSMethod 2—Tr=1.21 min (ES+) (M+H⁺) 321.0

[Intermediate 56]—2-[(2S)-1-phenylpiperazin-2-yl]propan-2-ol

Prepared analogously to the method of [Intermediate 54] from1-tert-butyl 3-methyl (3S)-4-phenylpiperazine-1,3-dicarboxylate (45 mg,0.14 mmol) to yield the crude title compound as a brown gel (29 mg,58%). LCMS Method 2—Tr=0.79 min (ES+) (M+H⁺) 221.15.

[Intermediate 57]—tert-Butyl3-(hydroxymethyl)-4-[2-(methylcarbamoyl)phenyl]piperazine-1-carboxylate

To a pressure tube of tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate (216 mg, 1 mmol),2-iodo-N-methyl benzamide (261 mg, 1 mmol), 2,3-butylene glycol (180 mg,2 mmol) and potassium phosphate (425 mg, 2 mmol) in isopropanol (2 mL).The reaction mixture was purged with nitrogen 5 mins and CuI (20 mg, 0.1mmol) was added. The reaction was stirred at 92° C. for 4 h. Aftercooling to rt, the reaction mixture was partitioned between MBTE (10 mL)and water (4 mL). The aqueous layer was extracted with MBTE (2×4 mL).The combined organic phases were dried (Na₂SO₄), filtered and reduced invacuo to yield a pale brown gum. The crude material was purified bypreparative HPLC [UV-Directed High pH prep method]. The productcontaining fractions were reduced in vacuo to afford the title compoundas colorless gum (73.1 mg, 20%). ¹H NMR (500 MHz, Chloroform-d) δ 9.19(s, 1H), 8.22 (dd, J=7.8, 1.9 Hz, 1H), 8.06 (s, 1H), 8.04 (s, 0.8H),7.50-7.36 (m, 1.8H), 7.29-7.22 (m, 2.6H), 7.11-7.00 (m, 0.8H), 7.00-6.91(m, 1H), 4.72 (hept, J=6.1 Hz, 0.8H), 4.14-3.94 (m, 1H), 3.94-3.75 (m,1H), 3.61-3.44 (m, 2H), 3.43-3.30 (m, 1H), 3.29-3.14 (m, 2H), 3.04 (dt,J=12.0, 3.6 Hz, 1H), 3.00 (s, 1.2H), 2.99 (s, 1.2H), 2.99 (s, 1.5H),2.98 (s, 1.5H), 2.82 (t, J=9.3 Hz, 1H), j 1.50 (s, 9H), 2.16 (s, 1H),1.42 (d, J=6.1 Hz, 4.8H). LCMS Method 5—Tr=1.20 min (ES+) (M+H⁺) 350.

[Intermediate 58]—2-[2-(hydroxymethyl)piperazin-1-yl]-N-methylbenzamidedihydrochloride

tert-Butyl3-(hydroxymethyl)-4-[2-(methylcarbamoyl)phenyl]piperazine-1-carboxylate[Intermediate 57] (36.4 mg, 0.104 mmol) was dissolved in dioxane (1 mL).To stirred reaction mixture was added 4M HCl in dioxane (1 mL). Thereaction mixture was stirred at rt for 2 h. The reaction mixture wasreduced to yield the tile compound white solid (33 mg, 99%)

[Intermediate 59]—tert-Butyl4-(2-cyanophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate

To a pressure tube of tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate (227 mg, 1.05 mmol),2-iodobenzonitrile (229 mg, 1 mmol), ethylene glycol (124 mg, 2 mmol)and K₃PO₄ (425 mg, 2 mmol) in isopropanol (2 ml) purged with nitrogenfor 5 mins, copper iodide (20 mg, 0.1 mmol) was added. The reaction washeated to 90° C. overnight. After cooling to ambient temperature MBTE (4ml) and water (2 ml) were added to the reaction mixture. The aqueouslayer was extracted with MBTE (2×4 ml). The combined organic phases werewashed with brine and dried over Na₂SO₄. The solvent was concentrated invacuo and the residue purified by flash column chromatography on silicagel (cyclohexane—50% MBTE) to yield the title compound as a colorlessgum (60.4 mg, 18%). LCMS Method 2—Tr=1.12 min, (ES+) (M+H⁺−^(t)Bu) 262,(M+Na⁺) 340. ¹H NMR (500 MHz, Chloroform-d) δ 7.64-7.57 (m, 1H),7.54-7.47 (m, 1H), 7.12-7.04 (m, 2H), 4.19-3.99 (m, 1H), 3.99-3.92 (m,1H), 3.92-3.80 (m, 1H), 3.80-3.68 (m, 1H), 3.68-3.45 (m, 2H), 3.46-3.39(m, 1H), 3.38-3.28 (m, 1H), 3.08 (dt, J=11.8, 3.3 Hz, 1H), 1.52 (s, 9H).

[Intermediate 60]—tert-Butyl3-(hydroxymethyl)-4-(pyridin-2-yl)piperazine-1-carboxylate

To a pressure tube; tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate(681 mg, 3.15 mmol), 2-iodopyridine (615 mg, 3 mmol), ethylene glycol(372 mg, 6 mmol) and potassium phosphate (1.28 g, 6 mmol) in isopropanol(6 ml) purged with nitrogen 5 mins were added then CuI (60 mg, 0.3 mmol)was added. The reaction was stirred and heated to 90° C. overnight.After cooling to ambient temperature MBTE (4 ml) and water (2 ml) werethen added to the reaction mixture. The organic layer was extracted withMBTE (2×4 ml). The combined organic phases were washed with brine anddried over Na₂SO₄. The solvent was concentrated in vacuo giving 918 mgof a green oil. Purified by flash column chromatography on silica gelusing gradient 0% to 100% MBTE in DCM. The product containing fractionswere combined and reduced in vacuo to yield the title compound as acolorless gum (143 mg, 9%).

Found by 1H NMR to be a ˜3:5 mixture of the title product and2-(pyridine-2-yloxy)ethan-1-ol. Used the crude product for the nextstage. ¹H NMR (500 MHz, Chloroform-d) δ 8.20-8.10 (m, 1.6H), 7.68-7.58(m, 1H), 7.57-7.47 (m, 0.6H), 6.97-6.89 (m, 1H), 6.87-6.80 (m, 1H),6.72-6.61 (m, 1.2H), 4.72-4.35 (m, 2.6H), 4.32-3.62 (m, 7H), 3.24 (d,J=7.7 Hz, 2H), 1.51 (s, 5.4H). LCMS Method 2—Tr=0.98 min, (ES+) (M+H⁺)294.

[Intermediate 61]—[1-(Pyridin-2-yl)piperazin-2-yl]methanolDihydrochloride

tert-Butyl 3-(hydroxymethyl)-4-(pyridin-2-yl)piperazine-1-carboxylate[Intermediate 60] (80 mg, 0.27 mmol) was dissolved in MeOH (3 ml) then12N. aq. HCl (1 ml) was added. The reaction was stirred overnight. Thereaction was evaporated to dryness below 30° C., to yield the titlecompound as a colorless gum (152 mg, 100%).

Found by 1H NMR to be a ˜3:5 mixture of the title product and2-(pyridine-2-yloxy)ethan-1-ol. Used as the mixture in the next step. ¹HNMR (500 MHz, DMSO-d6) δ 10.03-9.59 (s, 0.6H), 9.50-9.15 (m, 0.6H), 8.16(dd, J=5.1, 1.3 Hz, 1H), 8.08 (dd, J=6.0, 1.4 Hz, 0.6H), 8.05-7.94 (m,0.6H), 7.75 (ddd, J=8.9, 7.1, 2.0 Hz, 1H), 7.44-7.33 (m, 0.6H),7.05-6.94 (m, 1.6H), 6.91-6.82 (m, 1H), 4.69-4.64 (m, 0.6H), 4.38-4.30(m, 0.6H), 4.30-4.24 (m, 12H), 4.03-3.88 (m, 0.6H), 3.76-3.67 (m, 0.6H),3.73-3.67 (m, 2H), 3.62-3.51 (m, 0.6H), 3.48-3.44 (m, 0.6H), 3.39-3.30(m, 0.6H), 3.30-3.20 (m, 0.6H), 3.16-3.04 (m, 0.6H).

[Intermediate 62]—tert-Butyl4-(3-fluoro-2-sulfamoylphenyl)piperazine-1-carboxylate

A mixture of 2,6-difluorobenzene-1-sulfonamide (1 g, 5.18 mmol),tert-butyl piperazine-1-carboxylate (0.96 g, 5.18 mmol) and DIPEA (1.35ml, 7.77 mmol) in 1,4-dioxane (10 ml) was heated at 110° C. for 3 h. Thereaction mixture was evaporated and the residue purified by flash columnchromatography on a 50 g silica Biotage cartridge using a gradient of0-45% MBTE in DCM to yield the title compound as a crystalline solid.(796 mg, 39%). LCMS Method 2—Tr=1.13 mins, (ES+) (M+H⁺) 360.

[Intermediate 63]—tert-Butyl4-(5-fluoropyridin-2-yl)-3-oxopiperazine-1-carboxylate

Sodium hydride (144 mg, 6 mmol) was added to a stirred solution oftert-butyl 3-oxopiperazine-1-carboxylate (1 g, 5 mmol) in anhydrous DMF(8 ml) at 0-20° C. The reaction was then heated at 55° C. for 30 minutesand then allowed to cool. 2,5-Difluoropyridine (0.575 g, 5 mmol) wasadded and the mixture was stirred at 20° C. for 10 minutes then warmedto 60° C. for 20 h. The solution was diluted with DCM (40 ml), filteredthrough Celite, solids washed well with DCM and the filtrate was reducedin vacuo to yield the crude product. The crude product was purified viacolumn chromatography (25 g silica) eluted with a gradient of 0-100% DCMin MBTE. The product containing fraction were combined and reduced invacuo to yield the title compound as a pale brown gum. (254 mg, 17%). ¹HNMR (500 MHz, Chloroform-d) δ 8.28 (d, J=3.0 Hz, 1H), 8.10-7.95 (m, 1H),7.47 (ddd, J=9.1, 7.6, 3.0 Hz, 1H), 4.30 (s, 2H), 4.17-4.06 (m, 2H),3.87-3.71 (m, 2H), 1.52 (s, 9H). LCMS Method 2—Tr=1.07 mins, (ES+)(M+H⁺) 296.

[Intermediate 64]—tert-Butyl4-(2-fluorophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate

Prepared analogously to the method of tert-Butyl4-(2-cyanophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate[Intermediate 59] from tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate (216 mg, 1 mmol) and1-fluoro-2-iodobenzene (222 mg, 1 mmol) to yield the title compound as acolorless solid (194 mg, 63%). ¹H NMR (500 MHz, Chloroform-d) δ7.12-6.93 (m, 4H), 4.09-3.69 (m, 2H), 3.69-3.33 (m, 5H), 3.33-3.22 (m,1H), 3.02 (s, 1H), 1.49 (s, 9H). LCMS Method 2—Tr=1.17 mins, (ES+)(M+H⁺) 311.

[Intermediate 65]—tert-Butyl4-(3-fluorophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate

Prepared analogously to the method of tert-Butyl4-(2-cyanophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate[Intermediate 59] from tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate (216 mg, 1 mmol) and1-fluoro-3-iodobenzene (222 mg, 1 mmol) to yield the title compound as acolorless solid (181 mg, 58%). ¹H NMR (500 MHz, Chloroform-d) δ7.23-7.14 (m, 1H), 6.69-6.62 (m, 1H), 6.61-6.45 (m, 2H), 4.49-3.75 (m,3H), 3.75-3.24 (m, 3H), 3.20-2.94 (m, 3H), 2.69 (s, 1H), 1.49 (s, 9H).

LCMS Method 2—Tr=1.18 mins, (ES+) (M+H⁺) 310.

[Intermediate 66]—tert-Butyl4-(4-fluorophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate

Prepared analogously to the method of tert-Butyl4-(2-cyanophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate[Intermediate 59] from tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate (216 mg, 1 mmol) and1-fluoro-4-iodobenzene (205 mg, 1 mmol) to yield the title compound as acolorless solid (200 mg, 64%). ¹H NMR (500 MHz, Chloroform-d) δ7.02-6.93 (m, 2H), 6.93-6.77 (m, 2H), 4.37-3.94 (m, 1H), 3.90 (dtd,J=13.2, 3.7, 1.6 Hz, 1H), 3.82-3.23 (m, 4H), 3.28 (ddd, J=13.4, 9.6, 4.2Hz, 1H), 3.10 (d, J=13.2 Hz, 2H), 2.55 (br. s, 0.5H), 1.49 (s, 9H). LCMSMethod 2—Tr=1.13 mins, (ES+) (M+H⁺) 311.

[Intermediate 67]—tert-ButylN-[1-(5-fluoro-2-pyridyl)-4-piperidyl]carbamate

2,5-Difluoropyridine (250 mg, 2.17 mmol), tert-butylN-(4-piperidyl)carbamate (478 mg, 2.39 mmol) and K₂CO₃(300 mg, 2.17mmol) were suspended in DMF (2.5 ml) then the sealed reaction was heatedat 110° C. for 18 hours. The reaction mixture was diluted with 4:1EtOAc/heptane (10 ml) and water (10 ml). The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuo to yield the titlecompound as a yellow crystalline solid (433 mg, 61%). ¹H NMR (500 MHz,Chloroform-d)_8.02 (d, J=3.1 Hz, 1H), 7.22 (ddd, J=9.2, 7.8, 3.1 Hz,1H), 6.61 (dd, J=9.2, 3.3 Hz, 1H), 4.49 (s, 1H), 4.11-4.02 (m, 2H), 3.65(s, 1H), 2.98-2.89 (m, 2H), 2.01 (d, J=10.5 Hz, 2H), 1.44 (s, 11H). LCMSMethod 1—Tr=1.09 min (ES⁺) (M+H⁺) 296.

[Intermediate 68]—1-(5-Fluoro-2-pyridyl)piperidin-4-amine

tert-Butyl N-[1-(5-fluoro-2-pyridyl)-4-piperidyl]carbamate [Intermediate67] (5.0 g, 17.1 mmol) was dissolved in 50% TFA in DCM (30 ml) andstirred at ambient temperature for 16 hours. The reaction wasconcentrated in vacuo. The residue was dissolved in the minimum volumeof (1:1) MeOH/DCM. A glass column was charged with MP-TsOH (33 g, 103mmol) then the solution of crude product was loaded under gravity. Theresin was washed sequentially with DCM (200 ml), MeOH (200 ml), DCM (200ml) and MeOH (200 ml). The washings were discarded. The product was theneluted with 7N NH₃ in MeOH (400 ml). The NH₃ rinsing's were concentratedin vacuo to give the title compound as a beige solid (3.22 g, 93%yield). ¹H NMR (500 MHz, Chloroform-d) δ 8.02 (d, J=3.1 Hz, 1H), 7.22(ddd, J=9.2, 7.8, 3.1 Hz, 1H), 6.62 (dd, J=9.3, 3.3 Hz, 1H), 4.11 (dt,J=13.2, 2.9 Hz, 2H), 2.93-2.81 (m, 3H), 1.94-1.84 (m, 2H), 1.44-1.31 (m,4H). LCMS Method 5—Tr=0.65 min (ES⁺) (M+H⁺) 196.

[Intermediate 69]—tert-Butyl3-[[1-(5-fluoro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoate

1-(5-Fluoro-2-pyridyl)piperidin-4-amine [Intermediate 68] (1 g, 5.12mmol), tert-butyl 3-bromo-2,4,6-trimethyl-benzoate (1.53 g, 5.12 mmol),(+)-BINAP (0.8 g, 1.28 mmol), NaO^(t)Bu (0.98 g, 10.24 mmol) andPd₂(dba)₃ (0.47 g, 0.51 mmol) were suspended in toluene (5 ml). Thereaction was purged with nitrogen gas for 5 minutes then sealed andheated at 100° C. for 16 hours. The reaction was filtered through celiteand concentrated in vacuo. The crude residue was partitioned betweenEtOAc (25 ml) and water (25 ml) the organic layer was separated, washedwith brine (10 ml), dried (Na₂SO₄), filtered and concentrated in vacuo.The crude product was purified via flash column chromatography elutingwith a gradient from 0-100% EtOAc in heptane followed by 0-100% MeOH inEtOAc. The product containing fractions were combined and concentratedin vacuo to yield the title compound as a brown oil (1.09 g, 51%). ¹HNMR (500 MHz, Chloroform-d) δ 8.04 (d, J=3.1 Hz, 1H), 7.23 (ddd, J=9.2,7.8, 3.1 Hz, 1H), 6.83 (s, 1H), 6.62 (dd, J=9.2, 3.3 Hz, 1H), 4.17 (d,J=13.3 Hz, 2H), 3.04 (tt, J=11.0, 3.9 Hz, 1H), 2.80 (td, J=13.2, 2.4 Hz,3H), 2.27-2.20 (m, 10H), 2.04-1.94 (m, 2H), 1.60 (s, 11H), 1.44 (qd,J=12.3, 4.1 Hz, 2H). LCMS Method 5—Tr=4.13 min (ES⁺) (M+H⁺) 414.

[Intermediate70]—3-[[1-(5-Fluoro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid

A solution of tert-butyl3-[[1-(5-fluoro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoate[Intermediate 69] (1.09 g, 2.64 mmol) was dissolved in 4M HCl in dioxane(26 ml). The reaction mixture was stirred at ambient temperature for 16hours. The precipitate was isolated via filtration and washed with Et₂Oto yield the title compound as a pale yellow solid (1.80 g, 99%). ¹H NMR(500 MHz, Deuterium Oxide) 6 8.00 (ddd, J=10.1, 7.2, 2.9 Hz, 1H), 7.94(t, J=2.7 Hz, 1H), 7.40 (dd, J=10.2, 4.1 Hz, 1H), 7.25 (s, 1H), 4.25 (d,J=14.2 Hz, 2H), 3.91 (tt, J=11.9, 4.1 Hz, 1H), 3.76 (s, 4H), 3.30 (t,J=12.3 Hz, 2H), 2.46 (s, 3H), 2.41 (s, 3H), 2.34-2.25 (m, 5H), 2.06 (qd,J=12.5, 4.3 Hz, 2H). LCMS Method 5—Tr=2.19 min (ES⁺) (M+H⁺) 358.2

[Intermediate71]—(2S)-4-[(tert-Butoxy)carbonyl]-1-phenylpiperazine-2-carboxylic acid

1-tert-Butyl 3-methyl (3S)-4-phenylpiperazine-1,3-dicarboxylate[Intermediate 55] (90%, 2.1 g, 5.9 mmol) was suspended in MeOH (14 ml)then 2M aq. LiOH (6 ml) was added. The reaction mixture was sonicatedand THF (5 ml) was added. The solution was stirred for 16 hours atambient temperature. The mixture was concentrated in vacuo. Theresultant residue was taken up in DCM (20 ml) and partitioned with water(20 ml). The aqueous phase was acidified to pH 4 with aq. HCl and theorganic layer was then separated and concentrated in vacuo to afford thetitle compound as a white solid (1.7 g, 86%). ¹H NMR (250 MHz,Chloroform-d) δ 7.32-7.26 (m, 1H), 7.25-7.20 (m, 1H), 6.91-6.79 (m, 3H),4.51 (d, J=13.3 Hz, 1H), 4.40-4.32 (m, 1H), 4.09-3.96 (m, 1H), 3.58-3.27(m, 3H), 3.23-3.04 (m, 1H), 1.40 (s, 9H). LCMS Method 1—Tr=1.17 min,(ES+) (M+H⁺⁾ 307.1.

[Intermediate 72]—tert-Butyl(3S)-3-carbamoyl-4-phenylpiperazine-1-carboxylate

(2S)-4-[(tert-Butoxy)carbonyl]-1-phenylpiperazine-2-carboxylic acid[Intermediate 71] (91%, 1.7 g, 5.05 mmol), ammonium carbonate (0.68 g,7.07 mmol), HATU (2.3 g, 6.06 mmol) and DiPEA (2.05 ml, 11.8 mmol) weresuspended in DMF (12 ml) and stirred at ambient temperature for 16hours. The reaction mixture was concentrated in vacuo. The resultantresidue was partitioned between DCM (30 ml) and water (30 ml). Theorganic layer was separated and the aqueous phase extracted with DCM(2×15 ml). The organics were combined and concentrated in vacuo to givethe crude product. The crude product was purified via flash columnchromatography eluting with a gradient from 0-100% EtOAc in heptanefollowed by 0-100% MeOH in EtOAc. The fractions containing product wereconcentrated in vacuo to yield the title compound as a red solid (1.25g, 81%). ¹H NMR (250 MHz, Chloroform-d) δ 7.35-7.26 (m, 2H), 6.98-6.84(m, 3H), 6.41 (s, 1H), 5.55 (s, 1H), 4.15 (dd, J=13.1, 4.5 Hz, 1H),4.09-3.98 (m, 1H), 3.76-3.56 (m, 3H), 3.55-3.29 (m, 2H), 1.47 (s, 9H).LCMS Method 3—Tr=1.62 min, (ES+) (M+H⁺) 306.1.

[Intermediate 73]—(2S)-1-Phenylpiperazine-2-carboxamide

tert-Butyl (3S)-3-carbamoyl-4-phenylpiperazine-1-carboxylate[Intermediate 72] (1.25 g, 4.08 mmol) was suspended in 4M HCl in dioxane(15 ml) and the reaction mixture was stirred at ambient temperature for1 hour. 2M HCl in 1,4-dioxane (10 ml) was added and the mixture stirredfor 4 hours. The reaction mixture was concentrated in vacuo. Theresultant residue was loaded onto a Biotage SCX-2 column and washed withDCM/MeOH (100 ml), then eluted with 7N NH₃ in MeOH (100 ml). The eluatewas collected and concentrated in vacuo to afford the title compound asa beige solid (821 mg, 98%). ¹H NMR (250 MHz, DMSO-d6) δ 7.35 (s, 1H),7.27-7.11 (m, 3H), 6.96-6.86 (m, 2H), 6.77 (t, J=7.2 Hz, 1H), 4.35-4.22(m, 1H), 3.47-3.40 (m, 3H), 3.17 (s, 1H), 3.13-3.00 (m, 2H), 2.97-2.80(m, 1H). LCMS Method 3—Tr=1.25 min, (ES+) (M+H⁺) 206.2.

[Intermediate 74]—1-tert-Butyl 3-methyl(3S)-4-(4-fluorophenyl)piperazine-1,3-dicarboxylate

1-tert-Butyl 3-methyl (3S)-piperazine-1,3-dicarboxylate (10 g, 40.9mmol), (4-fluorophenyl)boronic acid (11.5 g, 82.1 mmol), copper(II)acetate (7.44 g, 40.9 mmol) and pyridine (6.67 ml, 82.6 mmol) weresuspended in anhydrous 1,2-dichloroethane (300 ml) and the mixture wasstirred at ambient temperature for 72 hours. A continuous airflow wasbubbled through the reaction and the mixture stirred for 44 hours atambient temperature. The airflow was removed and the reaction stirred at45° C. for 20 hours, then cooled to ambient temperature. The mixture wasfiltered through celite, washed with DCM. The filtrate was concentratedin vacuo and the green oil obtained was purified via flash columnchromatography eluting with gradient from 0-100% EtOAc in heptanefollowed by 0-100% MeOH in EtOAc. The product containing fractions werecombined and concentrated in vacuo to afford the title compound as ayellow oil (4.29 g, 29%). ¹H NMR (500 MHz, Chloroform-d) δ 6.98-6.92 (m,2H), 6.85-6.80 (m, 2H), 4.47 (d, J=12.7 Hz, 1H), 4.27 (s, 1H), 4.21-3.92(m, 1H), 3.64 (s, 3H), 3.60-3.47 (m, 1H), 3.37 (d, J=10.6 Hz, 1H),3.27-2.99 (m, 2H), 1.46 (s, 9H). LCMS Method 3 Tr=1.88 min, (ES+) (M+H⁺)339.1.

[Intermediate75]—(2S)-4-[(tert-Butoxy)carbonyl]-1-(4-fluorophenyl)piperazine-2-carboxylicAcid

1-tert-Butyl 3-methyl (3S)-4-(4-fluorophenyl)piperazine-1,3-dicarboxylate [Intermediate 74](93%, 4.29 g, 11.78 mmol) was suspended in MeOH (40 ml) and 2M aq. LiOH(12 ml). The mixture was stirred at ambient temperature for 75 hours.The MeOH was removed in vacuo and the aqueous suspension was acidifiedto pH 4 with 2M. aq. HCl and extracted with DCM (2×20 ml). The organicswere combined and concentrated in vacuo to afford the title compound asa yellow solid (4.07 g, 99%). ¹H NMR (250 MHz, Chloroform-d) δ 6.98-6.87(m, 2H), 6.84-6.73 (m, 2H), 4.44 (d, J=13.0 Hz, 1H), 4.18 (s, 1H), 4.03(d, J=11.8 Hz, 1H), 3.58-3.00 (m, 4H), 1.38 (s, 9H). LCMS Method3—Tr=1.25 min, (ES+) (M+H⁺) 325.2.

[Intermediate 76]—tert-Butyl(3S)-3-carbamoyl-4-(4-fluorophenyl)piperazine-1-carboxylate

(2S)-4-[(tert-Butoxy)carbonyl]-1-(4-fluorophenyl)piperazine-2-carboxylicacid [Intermediate 75] (93%, 4.07 g, 11.7 mmol), HATU (5.32 g, 14.0mmol), DiPEA (5.08 ml, 29.1 mmol) and ammonium carbonate (1.57 g, 16.3mmol) were suspended in 1,4-dioxane (40 ml) and DMF (10 ml). The mixturewas stirred at ambient temperature for 1 hour. The mixture wasconcentrated in vacuo. The resultant residue was partitioned between DCM(40 ml) and water (40 ml). The organic layer was separated and theaqueous phase extracted with DCM (2×20 ml). The organic layers werecombined and the solvents removed in vacuo. The solid obtained waspurified via flash column chromatography using gradients of 0 to 100%EtOAc in heptane, followed by 0 to 100% MeOH in EtOAc. The productcontaining fractions were combined and concentrated in vacuo to affordthe title compound as a white solid (1.61 g, 38%). ¹H NMR (500 MHz,DMSO-d6) δ 7.44 (s, 1H), 7.10-7.07 (m, 1H), 7.06-7.01 (m, 2H), 6.81-6.75(m, 2H), 4.11 (s, 1H), 4.04-3.99 (m, 1H), 3.76 (s, 1H), 3.57-3.47 (m,1H), 3.45-3.37 (m, 1H), 3.30-3.26 (m, 1H), 3.16 (s, 1H), 1.39 (s, 9H).LCMS Method 3—Tr=1.62 min, (ES+) (M+H⁺) 324.2.

[Intermediate 77]—(2S)-1-(4-Fluorophenyl)piperazine-2-carboxamide

tert-Butyl (3 S)-3-carbamoyl-4-(4-fluorophenyl)piperazine-1-carboxylate[Intermediate 76] (89%, 1.61 g, 4.44 mmol) was suspended in 4M HCl indioxane (15 ml). 1,4-dioxane (10 ml) was added and the mixture wasstirred for 1 hour at ambient temperature. 4M HCl in dioxane (5 ml) wasadded and the mixture was stirred for 18 hours. The reaction mixture wasconcentrated in vacuo. The resultant beige solid was taken up in MeOHand loaded onto a Biotage SCX-2 Column. The column was washed with MeOH(60 ml), then eluted with 7N NH₃ in MeOH (60 ml). The eluate wasconcentrated in vacuo to afford the title compound as a brown solid (910mg, 92%). ¹H NMR (250 MHz, Chloroform-d) δ 7.06-6.86 (m, 4H), 6.35 (s,1H), 5.49 (s, 1H), 3.92 (t, J=4.6 Hz, 1H), 3.38-3.15 (m, 3H), 3.13-2.93(m, 3H). LCMS Method 3—Tr=1.26 min, (ES+) (M+H⁺) 224.2.

[Intermediate 78]—Methyl (2R)-1-phenylpiperazine-2-carboxylate

1-tert-Butyl 3-methyl (3R)-4-phenylpiperazine-1,3-dicarboxylate[Intermediate 53] (1.13 g, 3.51 mmol) was suspended in a solution of 20%TFA in DCM (5 ml) and stirred at ambient temperature for 2 hours. TFA (1ml) was added and the reaction mixture was stirred for 3 hours. Sat aq.NaHCO₃(20 ml) was added and the reaction mixture was stirred for 5minutes, then 2M. aq. NaOH (5 ml) was added. The organic layer wasseparated and the aqueous phase was extracted with DCM (2×10 ml). Theorganics were combined and concentrated in vacuo to afford the titlecompound as a brown oil (749 mg, 97%). ¹H NMR (250 MHz, Chloroform-d) δ7.34-7.23 (m, 2H), 6.97-6.80 (m, 3H), 4.49-4.39 (m, 1H), 3.70 (s, 3H),3.60-2.83 (m, 6H), 2.34 (s, 1H). LCMS Method 3—Tr=1.47 min, (ES+) (M+H⁺)221.2.

[Intermediate 79]—[(2R)-1-Phenylpiperazin-2-yl]methanol

Methyl (2R)-1-phenylpiperazine-2-carboxylate [Intermediate 78] (749 mg,3.4 mmol) was suspended in anhydrous THF (10 ml) and stirred at 0° C.2.4M LiAlH₄ in THF (4.25 ml) was added dropwise and the mixture was thenstirred and allowed to warm to ambient temperature over 2 hours. Thereaction was stirred for 1.5 hours then cooled to 0° C. and 2.4M LiAlH₄in THF (1.5 ml) was added dropwise. The mixture was stirred for 1 hourat ambient temperature. The reaction was cooled to 0° C. and water (5.75ml) was added in a dropwise manner over 10 min. 15% aq. NaOH (5.75 ml)was added, followed by water (17.25 ml). The mixture was then filteredthrough celite (washing with EtOAc) and the filtrate was concentrated invacuo. The resultant residue was purified via flash columnchromatography using gradients of 0-100% MeOH in DCM. The productcontaining fractions were combined and concentrated in vacuo to affordthe title compound as a white solid (235 mg, 34%). ¹H NMR (250 MHz,Chloroform-d) δ 7.34-7.26 (m, 1H), 7.26-7.18 (m, 1H), 7.01-6.77 (m, 3H),4.33-4.21 (m, 2H), 4.05-3.70 (m, 3H), 3.46-2.82 (m, 6H). LCMS Method3—Tr=1.35 min, (ES+) (M+H⁺) 193.2.

[Intermediate 80]—tert-Butyl(3S)-4-(6-chloropyridazin-3-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

tert-Butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (4 g, 18.5mmol), 3,6-dichloropyridazine (2.75 g, 18.5 mmol) and Cs₂CO₃ (6.63 g,20.3 mmol) were suspended in toluene (10 ml). The reaction mixture wasstirred at 110° C. for 16 hours. The reaction mixture was concentratedin vacuo and the resultant residue was partitioned between DCM (50 ml)and water (50 ml). The organic layer was separated and dried over sodiumsulfate, filtered and concentrated in vacuo. The residue obtained waspurified via flash column chromatography using gradients of 0 to 100%EtOAc in heptane, followed by 0 to 100% MeOH in EtOAc. The productcontaining fractions were combined and concentrated in vacuo, and thesolid was washed with diethyl ether, then collected to afford the titlecompound as a white solid (1.69 g, 27%). ¹H NMR (500 MHz, Chloroform-d)δ 7.41 (d, J=9.2 Hz, 1H), 7.01 (d, J=9.2 Hz, 1H), 4.47 (d, J=37.8 Hz,2H), 3.96 (s, 1H), 3.19-3.12 (m, 1H), 3.04 (d, J=11.4 Hz, 1H), 3.00-2.88(m, 1H), 2.82 (td, J=11.4, 3.1 Hz, 2H), 1.49 (s, 10H). LCMS Method5—Tr=1.48 min (ES+) (M+H⁺) 329.1.

[Intermediate 81]—tert-Butyl(3S)-3-(hydroxymethyl)-4-(pyridazin-3-yl)piperazine-1-carboxylate

tert-Butyl (3S)-4-(6-chloropyridazin-3-yl)-3-(hydroxymethyl)piperazine-1—carboxylate[Intermediate 80] (1.69 g, 5.12 mmol) and 10% Pd/C (0.06 g, 0.56 mmol)were suspended in de-gassed ethanol (25 ml), and the mixture purgedthree times with nitrogen. The mixture was sealed under a hydrogenatmosphere and stirred at ambient temperature for 18 hours. The reactionmixture was filtered through celite, washing with EtOAc. The filtratewas concentrated in vacuo and the resultant oil was purified via flashcolumn chromatography using gradients of 0-100% MeOH in DCM. The productcontaining fractions were combined and concentrated in vacuo to affordthe title compound as a brown solid (1.4 g, 93%). ¹H NMR (250 MHz,Chloroform-d) δ 8.84 (d, J=4.0 Hz, 1H), 7.40 (dd, J=8.9, 4.4 Hz, 1H),7.20 (d, J=8.8 Hz, 1H), 4.87-4.69 (m, 2H), 4.19-3.94 (m, 3H), 3.61-3.49(m, 1H), 3.44-3.21 (m, 3H), 3.03-2.86 (m, 1H), 1.46 (s, 9H). LCMS Method3—Tr=1.54 min, (ES+) (M+H⁺) 295.2.

[Intermediate 82]—[(2S)-1-(Pyridazin-3-yl)piperazin-2-yl]methanol

tert-Butyl(3S)-3-(hydroxymethyl)-4-(pyridazin-3-yl)piperazine-1-carboxylate[Intermediate 81] (1.4 g, 4.76 mmol) was suspended in 4M HCl in Dioxane(5 ml) and stirred at ambient temperature for 1 hour. The reactionmixture was concentrated in vacuo to give a gray solid. The solid wasloaded onto a Biotage SCX-2 column and washed with (1:1) DCM/MeOH (30ml). The column was then eluted with 7N NH₃ in MeOH (50 ml) and theeluate collected and concentrated in vacuo to afford the title compoundas a yellow solid (950 mg, 82%) 1H NMR (500 MHz, DMSO-d6) δ 8.91 (dd,J=4.5, 1.2 Hz, 1H), 7.65 (dd, J=9.0, 4.5 Hz, 1H), 7.27-7.20 (m, 2H),4.44 (d, J=5.6 Hz, 2H), 3.30-3.19 (m, 3H), 3.16-3.10 (m, 1H), 3.08-3.02(m, 1H), 2.98-2.89 (m, 1H), 2.87-2.80 (m, 1H), 2.76 (t, J=11.7 Hz, 1H)

LCMS Method 3—Tr=1.03 min, (ES+) (M+H⁺) 195.2

[Intermediate 83]—1-tert-Butyl 3-methyl4-(4-fluorophenyl)piperazine-1,3-dicarboxylate

1-tert-Butyl 3-methyl piperazine-1,3-dicarboxylate (500 mg, 2.05 mmol),(4-fluorophenyl)boronic acid (575 mg, 4.11 mmol), copper(II) acetate(372 mg, 2.05 mmol) and pyridine (0.33 ml, 4.09 mmol) were suspended inanhydrous DCM (10 ml) with 4A molecular sieves (500 mg). The mixture wasstirred for 16 hours at ambient temperature, then for 5 hours at 35° C.Air was bubbled through the mixture for 10 min, then it was stirred for18 hours at ambient temperature. Air was bubbled through the mixture for10 min, then it was stirred at 35° C. for 6 hours and at ambienttemperature for 72 hours. Additional (4-fluorophenyl)boronic acid (286mg, 2.05 mmol) was added and the reaction was stirred for 4 hours at 35°C. The reaction was cooled to ambient temperature and filtered throughcelite. The filtrate was partitioned with sat. aq. NaHCO₃ (20 ml). Theorganic layer was separated and the aqueous extracted with DCM (2×20ml). The organics were combined and concentrated in vacuo to give agreen oil. The oil was purified via flash column chromatography using agradient of 0-50% EtOAc in heptane. The product containing fractionswere combined and concentrated in vacuo to afford the title compound asa yellow oil (213 mg, 26%). ¹H NMR (250 MHz, Chloroform-d) δ 7.01-6.90(m, 2H), 6.87-6.78 (m, 2H), 4.47 (d, J=13.4 Hz, 1H), 4.32-4.22 (m, 1H),4.09 (s, 1H), 3.63 (s, 3H), 3.59-3.46 (m, 1H), 3.37 (dd, J=13.3, 4.2 Hz,1H), 3.28-3.00 (m, 2H), 1.46 (s, 9H). LCMS Method 3—Tr=1.90 min, (ES+)(M+H⁺) 339.2.

[Intermediate84]—4-[(tert-Butoxy)carbonyl]-1-(4-fluorophenyl)piperazine-2-carboxylicAcid

1-tert-Butyl 3-methyl 4-(4-fluorophenyl)piperazine-1,3-dicarboxylate[Intermediate 83] (86%, 332 mg, 0.84 mmol) was taken up in (4:1)MeOH/water (5 ml) and 1M aq. LiOH (1.72 ml) was added. The reactionmixture was stirred at ambient temperature for 16 hours. 1M. aq. LiOH (1ml) was added and the reaction was stirred for 2 hours. IM. aq. LiOH (1ml) was added and the reaction was stirred for 3 hours. The MeOH wasremoved in vacuo and IM. aq. HCl (4.5 ml) was added. The aqueous mixturewas extracted with DCM (3×10 ml). The organics were combined, dried overMg₂SO₄, filtered, and concentrated in vacuo to afford the title compoundas a yellow solid (255 mg, 88%). +H NMR (250 MHz, Chloroform-d) δ7.00-6.90 (m, 2H), 6.86-6.76 (m, 2H), 4.47 (d, J=13.5 Hz, 1H), 4.27 (s,1H), 4.18-3.97 (m, 1H), 3.51 (td, J=11.4, 3.6 Hz, 1H), 3.37 (dd, J=13.4,4.3 Hz, 1H), 3.28-2.99 (m, 2H), 1.38 (s, 9H). LCMS Method 3—Tr=1.24 min,(ES+) (M+H⁺) 325.2.

[Intermediate 85]—tert-Butyl3-carbamoyl-4-(4-fluorophenyl)piperazine-1-carboxylate

4-[(tert-Butoxy)carbonyl]-1-(4-fluorophenyl)piperazine-2-carboxylic acid[Intermediate 84] (94%, 255 mg, 0.74 mmol), HATU (335 mg, 0.88 mmol) andDiPEA (300 μl, 1.72 mmol) were suspended in 1,4-dioxane (5 ml) and DMF(1 ml). The mixture was stirred at 40° C. for 1 hour, ammonium carbonate(90 mg, 0.94 mmol) was then added. The reaction mixture was stirred for2 hours at 40° C. The reaction mixture was concentrated in vacuo. Theresultant residue was partitioned between water (10 ml) and DCM (10 ml).The organic layer was separated and the aqueous extracted with DCM (10ml). The organics were combined, concentrated in vacuo and purified bypreparative HPLC [UV-Directed High pH prep method]. The fractionscontaining product were combined and concentrated in vacuo to afford thetitle compound as a white solid (117 mg, 49%). ¹H NMR (250 MHz,Chloroform-d) δ 7.08-6.81 (m, 4H), 6.33 (s, 1H), 5.53 (s, 1H), 3.96-3.65(m, 4H), 3.59-3.33 (m, 2H), 3.26-3.10 (m, 1H), 1.47 (s, 9H). LCMS Method3—Tr=1.63 min, (ES+) (M+H⁺) 324.2.

[Intermediate 86]—1-(4-Fluorophenyl)piperazine-2-carboxamide

tert-Butyl 3-carbamoyl-4-(4-fluorophenyl)piperazine-1-carboxylate[Intermediate 85] (117 mg, 0.36 mmol) was suspended in 4M HCl in Dioxane(1.5 ml) and stirred at ambient temperature for 4 hours, then leftstanding for 16 hours. 4M HCl in Dioxane (1 ml) was added and thereaction was stirred for 3 hours. The mixture was concentrated in vacuoand the solid obtained was taken up in DCM (5 ml) and washed with 2M.aq. NaOH (5 ml). The organic layer was concentrated in vacuo to affordthe title compound as a white solid (96 mg, 100%). ¹H NMR (250 MHz,Chloroform-d) δ 7.07-6.86 (m, 4H), 6.34 (s, 1H), 5.43 (s, 1H), 3.97-3.87(m, 1H), 3.38-3.15 (m, 3H), 3.14-2.93 (m, 3H). LCMS Method 3—Tr=1.28min, (ES+) (M+H⁺) 224.3.

[Intermediate 87]—tert-Butyl(3S)-4-(2-cyano-4-nitro-phenyl)-3-(hydroxymethyl)piperazine-1-carboxylate

tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.5 g, 11.56mmol), 2-fluoro-5-nitro-benzonitrile (1.92 g, 11.6 mmol) and DiPEA (2.47ml, 13.9 mmol) were dissolved in 1,4-dioxane (25 ml). The reaction washeated to 80° C. for 24 hours then increased to 90° C. for a further 18hours. The reaction was concentrated in vacuo. The residue obtained waspurified via flash column chromatography using gradients of 0 to 100%EtOAc in heptane, followed by 0 to 100% MeOH in EtOAc. The fractionscontaining product were combined and concentrated in vacuo to afford thetitle compound as a yellow gel (4.07 g, 67%).

LCMS Method 3—Tr=0.61 min (ES+) (M+H⁺) 363.2

[Intermediate 88]—tert-Butyl(3S)-4-(4-amino-2-cyano-phenyl)-3-(hydroxymethyl)piperazine-1-carboxylate

Crude tert-butyl(3S)-4-(2-cyano-4-nitro-phenyl)-3-(hydroxymethyl)piperazine-1-carboxylate[Intermediate 87] (4.08 g, 11.2 mmol), ammonium chloride (3.61 g, 67.5mmol) and Fe (3.14 g, 56.2 mmol) were suspended in (1:1) MeOH/water (75ml) then the reaction was heated at 80° C. for 3 hours. The reactionmixture was cooled and filtered through celite. The filtrate wasconcentrated in vacuo to remove the bulk of the organics. The resultantresidue was extracted with DCM (30 ml). The organics were dried overNa₂SO₄, filtered and concentrated in vacuo to afford the title compoundas a brown solid (3.55 g, 100%). LCMS Method 1—Tr=0.98 min (ES+) (M+H⁺)333.05.

[Intermediate 89]—tert-Butyl(3S)-4-(4-amino-2-cyano-phenyl)-3-(hydroxymethyl)piperazine-1-carboxylate

tert-Butyl (3S)-4-(4-amino-2-cyano-phenyl)-3-(hydroxymethyl)piperazine-1-carboxylate[Intermediate 88] (3.74 g, 11.2 mmol) was treated with pre-cooled (0°C.) 50% aq. hypophosphorous acid (50 ml). The reaction was stirred for10 mins at 0° C. and NaNO₂ (1.94 g, 28.11 mmol) was added and stirredfor 45 minutes at 0° C. The reaction had given rise to a sticky residuewhich retarded stirring. 1,4-Dioxane (50 ml) was chilled then added tothe reaction and was then stirred at 0° C. for 2 hours. NaHCO₃ (35 g,416.6 mmol) was suspended in water (100 ml) then the reaction was slowlyadded to the suspension. TBME (50 ml) was added and the biphasicsolution was separated and the organics were dried over Na₂SO₄, filteredand concentrated in vacuo. The residue obtained was purified via flashcolumn chromatography using gradients of 0 to 100% EtOAc in heptane,followed by 0 to 100% MeOH in EtOAc. The fractions containing productwere combined and concentrated in vacuo to afford the title compound asa light orange oil (2.47 g, 72%). ¹H NMR (500 MHz, DMSO-d6) δ 7.69 (dd,J=7.7, 1.6 Hz, 1H), 7.59 (ddd, J=8.9, 7.5, 1.6 Hz, 1H), 7.24 (d, J=8.3Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 4.63 (s, 1H), 3.80 (s, 2H), 3.66 (dd,J=8.1, 4.3 Hz, 1H), 3.39 (d, J=11.4 Hz, 2H), 3.27-3.09 (m, 2H), 3.01(dd, J=8.6, 3.9 Hz, 1H), 1.43 (s, 9H), 1.31-1.18 (m, 1H). LCMS Method1—Tr=1.15 min (ES+) (M+H⁺) 318.1.

[Intermediate 90]—2-[(2S)-2-(Hydroxymethyl)piperazin-1-yl]benzonitrile

tert-Butyl (3S)-4-(2-cyanophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate[Intermediate 89] (2.47 g, 7.77 mmol) was suspended in 20% TFA in DCM(25 ml). The reaction mixture was agitated for 18 hours. The reactionwas concentrated in vacuo then the residue was taken up in (1:1)DCM/MeOH and loaded onto a 20 g SCX-2 column. The column was then washedwith (1:1) DCM/MeOH (100 ml), then the product was eluted with 2.8M NH₃in (1:1) DCM/MeOH [40 ml 7N NH₃ in MeOH, 10 ml MeOH, 50 ml DCM] whichwas subsequently concentrated in vacuo. The resultant residue obtainedwas purified via flash column chromatography using gradients of 0 to100% EtOAc in heptane, followed by 0 to 100% MeOH in EtOAc. Thefractions containing product were combined and concentrated in vacuo toafford the title compound as a pale yellow oil (930 mg, 55%). ¹H NMR(500 MHz, DMSO-d6) δ 7.63 (dd, J=7.7, 1.6 Hz, 1H), 7.54 (ddd, J=8.8,7.5, 1.7 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.04-6.99 (m, 1H), 4.51 (s,1H), 3.66 (q, J=8.2, 7.6 Hz, 1H), 3.62 (dd, J=8.1, 4.0 Hz, 1H),3.23-3.15 (m, 1H), 2.97-2.91 (m, 2H), 2.88 (d, J=8.8 Hz, 2H), 2.75-2.68(m, 1H), 2.52-2.50 (m, 1H), 2.25 (s, 1H). LCMS Method 3—Tr=1.37 min(ES+) (M+H⁺) 218.2.

[Intermediate91]—2,4,6-trimethyl-3-{[1-(pyrazin-2-yl)piperidin-4-yl]amino}benzoylChloride Hydrochloride

2,4,6-Trimethyl-3-[(1-pyrazin-2-yl-4-piperidyl)amino]benzoic acid[Intermediate 101] (120 mg, 0.35 mmol) was suspended in toluene (2 ml)then SOCl₂ (103 μl, 1.41 mmol) was added and the sealed reaction washeated at 70° C. 1,4-dioxane (1.0 ml) was added and the reaction heatedfor 1.5 hours. SOCl₂ (103 μl, 1.41 mmol) was added and the reaction washeated at 70° C. for 4 hours. The reaction was then concentrated invacuo to yield the title compound as a straw yellow solid (113 mg, 81%).¹H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.11-8.08 (m, 1H), 7.83 (d,J=2.6 Hz, 1H), 7.27-7.14 (m, 1H), 7.06 (s, 1H), 4.41 (d, J=13.2 Hz, 2H),2.90 (t, J=12.0 Hz, 2H), 2.38 (s, 2H), 2.33 (s, 2H), 2.27 (d, J=23.1 Hz,1H), 2.21 (s, 3H), 2.13 (d, J=20.5 Hz, 1H), 1.97-1.87 (m, 2H), 1.75 (s,2H).

[Intermediate92]—3-{[1-(5-fluoropyridin-2-yl)piperidin-4-yl]amino}-2,4,6-trimethylbenzoylChloride Hydrochloride

3-[[1-(5-Fluoro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid [Intermediate 70] (100 mg, 0.27 mmol) was suspended in 1:1toluene/1,4-dioxane (2.0 ml) then thionyl chloride (97 μl, 1.33 mmol)was added and the sealed reaction was heated at 70° C. for 18 hours. Thereaction was concentrated in vacuo to yield the title compound as anoff-white solid (103 mg, 98%). ¹H NMR (500 MHz, DMSO-d6) δ 8.09 (d,J=3.1 Hz, 1H), 7.53 (td, J=9.2, 3.1 Hz, 1H), 7.08 (s, 1H), 6.93 (dd,J=9.4, 3.4 Hz, 1H), 4.27 (d, J=13.4 Hz, 2H), 2.82 (t, J=12.3 Hz, 2H),2.38 (s, 3H), 2.33 (s, 3H), 2.21 (s, 3H), 1.95-1.84 (m, 2H), 1.75 (s,2H).

[Intermediate93]—3-{[1-(2-cyano-4-fluorophenyl)piperidin-4-yl]amino}-2,4,6-trimethylbenzoylChloride Hydrochloride

Prepared analogously to the method for [Intermediate 92] from3-[[1-(2-Cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid hydrochloride [Intermediate 100] (103 mg, 0.27 mmol) to yield thetitle compound as an orange solid (149 mg, 85%). LCMS Method 1[submitted in MeOH]—Tr=1.32 min (ES+) (M+H⁺) 396.15 (methyl esteranalogue)

[Intermediate 94]—tert-Butyl 3-bromo-2,4,6-trimethylbenzoate

2,4-dibromo-1,3,5-trimethylbenzene (50 g, 180 mmol) was dissolved inanhydrous Et₂O (400 ml). The reaction mixture was cooled to −40° C. and1.6M n-BuLi in hexane (130 ml, 208 mmol) was added dropwise over 45minutes. The reaction mixture was stirred for 2 hour at −40° C.Di-tert-butyl dicarbonate (41 g, 188 mmol) was added to the reactionmixture at −40° C. and the reaction was stirred at −40° C. for 1 hour.The reaction mixture was quenched with 10% aq. citric acid (500 ml). Thereaction mixture was warmed to ambient temperature and extracted withEtOAc (×2). The organics were combined and washed with brine, dried overMgSO₄, filtered and reduced in vacuo to yield the crude product as anoff-white solid. The crude product was dissolved in heptane and waspurified via flash column chromatography using a gradient of 0 to 50%DCM in heptane to yield the title compound as a white crystalline solid(15 g, 26%). ¹H NMR (250 MHz, Chloroform-d) δ 6.94 (s, 1H), 2.41 (d,J=5.7 Hz, 6H), 2.27 (s, 3H), 1.69-1.59 (m, 9H). LCMS Method 4—Tr=5.80min (ES+) (M+H⁺) no mass ion seen.

[Intermediate 95]—tert-butyl2,4,6-trimethyl-3-{[1-(pyrazin-2-yl)piperidin-4-yl]amino}benzoate

tert-Butyl 3-bromo-2,4,6-trimethyl-benzoate [Intermediate 94] (1.25 g,4.18 mmol), 1-pyrazin-2-ylpiperidin-4-amine dihydrochloride (1.15 g, 4.6mmol), Pd(dba)₂ (0.12 g, 0.21 mmol), (±)-BINAP (0.33 g, 0.52 mmol) andNaOtBu (1.69 g, 17.6 mmol) were suspended in nitrogen degassed toluene(20 ml) then the reaction was heated at 110° C. for 18 hours. Thereaction mixture was partitioned between EtOAc (100 ml) and water (100ml). The organics were separated, washed water, dried over Na₂SO₄,filtered and concentrated in vacuo. The resultant residue was purifiedvia flash column chromatography using gradients of 0 to 100% EtOAc inheptane, followed by 0 to 100% MeOH in EtOAc. The fractions containingproduct were combined and concentrated in vacuo to afford the titlecompound as a tan viscous oil (1.74 g, 100%). ¹H NMR (500 MHz, DMSO-d6)8.31 (d, J=1.4 Hz, 1H), 8.05 (dd, J=2.5, 1.5 Hz, 1H), 7.78 (d, J=2.6 Hz,1H), 6.82 (s, 1H), 4.32 (d, J=13.4 Hz, 2H), 3.66 (d, J=10.4 Hz, 1H),2.99 (dq, J=7.8, 5.4, 3.7 Hz, 1H), 2.87 (t, J=11.8 Hz, 2H), 2.19 (s,3H), 2.14 (s, 3H), 2.12 (s, 3H), 1.79 (d, J=10.2 Hz, 2H), 1.53 (s, 9H),1.44 (qd, J=12.0, 11.6, 3.5 Hz, 2H). LCMS Method 1—Tr=1.26 min (ES+)(M+H⁺) 397.25.

[Intermediate 96]—tert-ButylN-[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]carbamate

tert-Butyl N-(4-piperidyl)carbamate (10 g, 49.9 mmol),2,5-difluorobenzonitrile (7.29 g, 52.4 mmol) and K₂CO₃ (8.28 g, 59.9mmol) were suspended in DMF (100 ml) then the reaction was heated to110° C. for 18 hours. The reaction was cooled then partitioned betweenwater (200 ml) and (3:1) EtOAc/Hept (200 ml). The organics wereseparated, the aqueous layer extracted with (3:1) EtOAc/Hept (100 ml).The organics were combined, washed with brine (200 ml), dried overNa₂SO₄, filtered and concentrated in vacuo. The resultant residue waspurified via flash column chromatography using gradients of 0 to 100%EtOAc in heptane, followed by 0 to 100% MeOH in EtOAc. The fractionscontaining product were combined and concentrated in vacuo to afford thetitle compound as a white powdery solid (7.29 g, 44%). ¹H NMR (500 MHz,DMSO-d6) δ 7.69 (dd, J=8.4, 3.1 Hz, 1H), 7.48 (td, J=8.7, 3.1 Hz, 1H),7.21 (dd, J=9.2, 4.7 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 3.39 (s, 1H), 2.80(t, J=10.8 Hz, 2H), 1.84 (d, J=10.6 Hz, 2H), 1.56 (qd, J=12.1, 3.9 Hz,2H), 1.39 (s, 9H). LCMS Method 1—Tr=1.23 min (ES+) (M+H⁺) 320.0.

[Intermediate 97]—2-(4-Amino-1-piperidyl)-5-fluoro-benzonitrilehydrochloride

tert-Butyl N-[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]carbamate[Intermediate 96] (7.29 g, 22.8 mmol) was taken up in 4M HCl in1,4-dioxane (80 ml) and agitated for 30 mins. 1,4-Dioxane (80 ml) wasadded and the reaction mixture was agitated for 2 hours. The reactionwas diluted with TBME (250 ml) and sonicated then filtered. The filtercake was washed with TBME (250 ml×2), MeCN (250 ml) and dried in vacuoto yield the title compound as a pale creme solid (5.30 g, 91%). ¹H NMR(500 MHz, DMSO-d6) δ 8.08 (s, 3H), 7.73 (dd, J=8.4, 3.1 Hz, 1H), 7.51(td, J=8.7, 3.1 Hz, 1H), 7.22 (dd, J=9.1, 4.7 Hz, 1H), 3.41 (d, J=12.5Hz, 2H), 3.24-3.12 (m, 1H), 2.84 (t, J=11.2 Hz, 2H), 2.04 (d, J=10.1 Hz,2H), 1.72 (qd, J=12.1, 3.9 Hz, 2H). LCMS Method 3—Tr=1.68 min (ES+)(M+H⁺) 220.2.

[Intermediate 98]—tert-Butyl3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoate

Prepared analogously to [Intermediate 95] from tert-butyl3-bromo-2,4,6-trimethyl-benzoate [Intermediate 94] (6.09 g, 20.3 mmol)and 2-(4-amino-1-piperidyl)-5-fluoro-benzonitrile hydrochloride[Intermediate 99] (5.2 g, 20.3 mmol) to yield the title compound as astraw viscous oil (8.25 g, 74%). ¹H NMR (500 MHz, DMSO-d6) δ 7.68 (dd,J=8.4, 3.1 Hz, 1H), 7.47 (td, J=8.7, 3.1 Hz, 1H), 7.18 (dd, J=9.2, 4.7Hz, 1H), 6.82 (s, 1H), 3.75 (d, J=10.5 Hz, 1H), 3.37 (d, J=12.2 Hz, 2H),3.31 (s, 6H), 2.76 (t, J=11.1 Hz, 2H), 2.21 (d, J=9.3 Hz, 5H), 2.16 (s,3H), 2.12 (s, 3H), 1.85 (d, J=10.4 Hz, 2H), 1.68 (qd, J=12.2, 3.8 Hz,2H), 1.24 (qq, J=14.3, 6.6, 5.7 Hz, 3H), 0.91-0.75 (m, 4H). LCMS Method1—Tr=1.47 min (ES+) (M+H⁺) 438.55.

[Intermediate 99]—tert-Butyl2,4,6-trimethyl-3-[(1-pyridazin-3-yl-4-piperidyl)amino]benzoate

Prepared analogously to [Intermediate 95] from tert-butyl3-bromo-2,4,6-trimethyl-benzoate [Intermediate 94] (5.0 g, 16.7 mmol)and 1-pyridazin-3-ylpiperidin-4-amine (3.28 g, 18.38 mmol) to yield thetitle compound as a brown oil (7.64 g, 83%). LCMS Method 1—Tr=0.98 min(ES+) (M+H⁺) 397.55.

[Intermediate100]—3-[[1-(2-Cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicAcid Hydrochloride

tert-Butyl3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoate[Intermediate 98] (8.25 g, 18.9 mmol) was dissolved/suspended in1,4-dioxane (40 ml). 4M HCl in 1,4-dioxane (160 ml) was added and leftto stand with occasional agitation. The reaction mixture wasconcentrated in vacuo to yield the crude product as an oil. TBME (˜150ml) was gradually added, then the reaction was sonicated to give rise toan off-white suspension. The suspension was filtered, the filter cakewas washed with TBME. The solid was dried in vacuo to yield the titlecompound as a tan solid (7.47 g, 92%). ¹H NMR (500 MHz, DMSO-d6) δ 7.72(dd, J=8.4, 3.1 Hz, 1H), 7.49 (td, J=8.7, 3.1 Hz, 1H), 7.19 (dd, J=9.2,4.7 Hz, 1H), 7.05 (s, 1H), 3.57 (s, 1H), 3.21 (s, 2H), 2.81 (t, J=10.8Hz, 2H), 2.42-2.30 (m, 6H), 2.21 (s, 3H), 1.98 (s, 4H). LCMS Method3—Tr=1.29 min (ES+) (M+H⁺) 382.1.

[Intermediate101]—2,4,6-Trimethyl-3-[(1-pyrazin-2-yl-4-piperidyl)amino]benzoic aciddihydrochloride

Prepared analogously to [Intermediate 100] from tert-butyl2,4,6-trimethyl-3-{[1-(pyrazin-2-yl)piperidin-4-yl]amino}benzoate[Intermediate 95] (1.74 g, 4.39 mmol) to yield the title compound as ayellow powdery solid (1.87 g, 100%). ¹H NMR (500 MHz, DMSO-d6) δ 8.37(d, J=1.3 Hz, 1H), 8.10 (dd, J=2.5, 1.5 Hz, 1H), 7.83 (d, J=2.6 Hz, 1H),7.10 (s, 1H), 4.42 (d, J=13.4 Hz, 2H), 3.72-3.65 (m, 1H), 2.90 (t,J=12.2 Hz, 2H), 2.41 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 1.95 (d,J=10.6 Hz, 2H), 1.78 (d, J=10.3 Hz, 2H). LCMS Method 3—Tr=1.19 min (ES+)(M+H⁺) 341.2.

[Intermediate102]—2,4,6-Trimethyl-3-{[1-(pyridazin-3-yl)piperidin-4-yl]amino}benzoicAcid Dihydrochloride

Prepared analogously to [Intermediate 100] from tert-butyl2,4,6-trimethyl-3-[(1-pyridazin-3-yl-4-piperidyl)amino]benzoate[Intermediate 99] (72%, 7.63 g, 13.9 mmol) to yield the title compoundas a pale yellow powdery solid (8.55 g, 100%). ¹H NMR (500 MHz, DMSO-d6)S 8.70 (d, J=4.2 Hz, 1H), 8.00 (d, J=9.5 Hz, 1H), 7.91 (dd, J=9.6, 4.5Hz, 1H), 7.00 (s, 1H), 4.38 (d, J=13.3 Hz, 2H), 3.19-3.10 (m, 3H), 2.34(d, J=21.2 Hz, 6H), 2.20 (s, 3H), 1.97 (d, J=10.8 Hz, 2H), 1.78 (s, 2H).LCMS Method 1—Tr=0.70 min (ES+) (M+H⁺) 341.15.

[Intermediate 103]—tert-ButylN-[1-(2-cyano-6-fluorophenyl)piperidin-4-yl]carbamate

2,3-Difluorobenzonitrile (1.25 g, 8.99 mmol) and K₂CO₃ (1.49 g, 10.78mmol) were suspended in DMF (10 ml) then tert-butylN-(piperidin-4-yl)carbamate (1.8 g, 8.99 mmol) was added and the mixturewas heated at 110° C. for 16 hours. The cooled reaction was diluted withwater (40 ml) and extracted with DCM (3×30 ml) then the combinedorganics were washed with brine (50 ml), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified via flash columnchromatography eluting with a gradient of 10% to 100% EtOAc in heptaneto yield the title compound (2.12 g, 74%). ¹H NMR (500 MHz,Chloroform-d) δ 7.34 (d, J=7.7 Hz, 1H), 7.20 (ddd, J=12.2, 8.2, 1.4 Hz,1H), 7.04-6.97 (m, 1H), 4.51 (s, 1H), 3.65 (s, 1H), 3.38 (d, J=12.2 Hz,2H), 3.25 (t, J=11.8 Hz, 2H), 2.04 (d, J=10.2 Hz, 2H), 1.69-1.58 (m,2H), 1.46 (s, 9H). LCMS Method 1—Tr=1.28 min (ES+) (M+H⁺) 320.1.

[Intermediate 104]—2-(4-Aminopiperidin-1-yl)-3-fluorobenzonitrile

tert-Butyl N-[1-(2-cyano-6-fluorophenyl)piperidin-4-yl]carbamate[Intermediate 103] (2.11 g, 6.61 mmol) was dissolved in MeOH (8 ml) and4M HCl in 1,4-dioxane (8.26 ml) was added. The reaction mixture wasstirred at ambient temperature for 16 hours. The reaction wasconcentrated in vacuo and the resultant residue was taken up in MeOH andloaded onto an SCX-2 cartridge (20 g) which was washed with MeOH. Theproduct was eluted using 7N NH₃ in MeOH. The NH₃/MeOH eluate wasconcentrated in vacuo to yield the title compound (1.43 g, 99%). ¹H NMR(500 MHz, Chloroform-d) δ 7.26 (s, 1H), 7.18 (ddd, J=9.0, 7.9, 3.1 Hz,1H), 6.99 (dd, J=9.1, 4.6 Hz, 1H), 3.50-3.37 (m, 2H), 2.94-2.75 (m, 3H),2.04-1.88 (m, 2H), 1.69-1.56 (m, 2H). LCMS Method 3—Tr=3.16 min (ES+)(M+H⁺) 219.9.

[Intermediate105]—2,4,6-Trimethyl-3-{[1-(pyridazin-3-yl)piperidin-4-yl]amino}benzoylchloride hydrochloride

Prepared analogously to [Intermediate 92]2,4,6-Trimethyl-3-{[1-(pyridazin-3-yl)piperidin-4-yl]amino}benzoic aciddihydrochloride [Intermediate 102] to yield the title compound as alight tan solid (505 mg, 96%). ¹H NMR (500 MHz, DMSO-d6) 8.74 (d, J=3.9Hz, 1H), 8.06 (d, J=9.5 Hz, 1H), 7.97 (dd, J=9.6, 4.5 Hz, 1H), 7.07 (s,1H), 4.42 (d, J=13.5 Hz, 3H), 3.62 (s, 1H), 3.16 (t, J=12.6 Hz, 2H),2.44 (s, 3H), 2.38 (s, 3H), 2.22 (s, 3H), 2.03 (d, J=10.9 Hz, 2H), 1.90(d, J=11.4 Hz, 2H), 1.24 (s, 1H). LCMS Method 1 [submitted inMeOH]—Tr=0.87 min (ES+) (M+H⁺) 355.2—mass ion of methyl ester.

[Intermediate 106]—Benzyl4-(3-tert-butoxycarbonyl-2,4,6-trimethyl-anilino)piperidine-1-carboxylate

tert-Butyl 3-bromo-2,4,6-trimethyl-benzoate [Intermediate 94] (1 g, 3.34mmol), benzyl 4-aminopiperidine-1-carboxylate (0.78 g, 3.34 mmol),(+)-BINAP (0.52 g, 0.84 mmol), NaO^(t)Bu (0.64 g, 6.68 mmol) andPd₂(dba)₃ (0.31 g, 0.33 mmol) were suspended in toluene (10 ml). Thereaction mixture was heated at 100° C. for 16 hours. The reaction wasfiltered through celite and concentrated in vacuo. The crude waspurified via flash column chromatography using a gradient of 0% to 100%EtOAc in heptane followed by 0% to 100% MeOH in EtOAc. The productcontaining fractions were combined and concentrated in vacuo to give thetitle compound as a yellow oil (830 mg, 53%). ¹H NMR (500 MHz,Chloroform-d) δ 7.39-7.29 (m, 5H), 6.82 (s, 1H), 5.13 (s, 2H), 4.27-4.10(m, 2H), 2.97 (tt, J=10.9, 3.8 Hz, 1H), 2.76 (s, 3H), 2.23 (s, 3H), 2.22(s, 3H), 2.21 (s, 3H), 1.91 (s, 2H), 1.59 (s, 9H), 1.36-1.30 (m, 2H).LCMS Method 5—Tr 4.43 min (ES⁺) (M+H⁺) 453.

[Intermediate107]—3-[(1-Benzyloxycarbonyl-4-piperidyl)amino]-2,4,6-trimethyl-benzoicAcid

Benzyl4-(3-tert-butoxycarbonyl-2,4,6-trimethyl-anilino)piperidine-1-carboxylate[Intermediate 106] (860 mg, 1.9 mmol) was dissolved in 4M HCl in1,4-dioxane (19 ml), the reaction mixture was stirred at ambienttemperature for 16 hours. The precipitate was isolated via filtration.The filter cake was purified via reverse phase column chromatography[C18] using a gradient from 0% to 100% acetonitrile (with 1% formic acidmodifier) in water (with 1% formic acid modifier). The productcontaining fractions were combined and concentrated in vacuo to give thetitle compound as a white solid (538 mg, 56%). ¹H NMR (500 MHz,Chloroform-d) δ 7.42-7.28 (m, 5H), 6.87 (s, 1H), 5.13 (s, 2H), 4.19 (s,2H), 3.01 (tt, J=11.1, 3.8 Hz, 1H), 2.76 (s, 2H), 2.35-2.26 (m, 6H),2.23 (s, 3H), 1.98-1.84 (m, 2H), 1.41-1.23 (m, 2H). LCMS Method 5—Tr2.87 min (ES⁺) (M+H⁺) 397.

[Intermediate 108]—Benzyl4-[3-[(3S)-3-(hydroxymethyl)-4-phenyl-piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]piperidine-1-carboxylate

3-[(1-Benzyloxycarbonyl-4-piperidyl)amino]-2,4,6-trimethyl-benzoic acid[Intermediate 107] (76%, 480 mg, 0.92 mmol),[(2S)-1-phenylpiperazin-2-yl]methanol [Intermediate 119] (230 mg, 1.2mmol), HATU (385 mg, 1.01 mmol) and DiPEA (714 mg, 5.52 mmol) weresuspended in NMP (5 ml). The reaction was heated at 50° C. for 16 hours.The reaction was concentrated in vacuo and the residue was purified viaflash column chromatography using a gradient of 0% to 100% EtOAc inheptane. The product containing fractions were combined and concentratedin vacuo to give the title compound as a brown oil (230 mg, 42%). ¹H NMR(500 MHz, Chloroform-d) δ 7.39-7.26 (m, 7H), 6.98-6.83 (m, 4H), 5.12 (d,J=2.4 Hz, 2H), 4.35-4.15 (m, 2H), 4.08-4.01 (m, 1H), 3.78-3.21 (m, 7H),3.10-2.96 (m, 2H), 2.75 (s, 2H), 2.27-2.19 (m, 6H), 2.13 (s, 3H),1.98-1.84 (m, 2H), 1.57 (s, 2H), 1.38-1.28 (m, 2H). LCMS Method 5—Tr3.26, 3.41, 3.54, 3.61 min (ES+) (M+H⁺) 571.

[Intermediate109]—[(3S)-3-(Hydroxymethyl)-4-phenyl-piperazin-1-yl]-[2,4,6-trimethyl-3-(4-piperidylamino)phenyl]methanone

Benzyl4-[3-[(3S)-3-(hydroxymethyl)-4-phenyl-piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]piperidine-1-carboxylate[Intermediate 108] (50 mg, 0.09 mmol) was dissolved in nitrogen purgedethanol (2 ml). The reaction flask was purged three times with nitrogenbefore 5% Pd/C (18.7 mg, 0.01 mmol) was added. The reaction was purgedwith nitrogen three times before being sealed under a hydrogenatmosphere. The reaction was stirred at ambient temperature for 5 hours.The reaction mixture was filtered through celite and concentrated invacuo to give a crude product as an oil. The oil was purified viapreparative HPLC [UV-directed High pH prep method]. The productcontaining fractions were combined and concentrated in vacuo to give thetitle compound as a pale yellow oil (25 mg, 62%). ¹H NMR (500 MHz,Chloroform-d) δ 7.31-7.23 (m, 2H), 6.98-6.82 (m, 4H), 4.80-3.99 (m, 2H),3.78-3.19 (m, 7H), 3.12-2.90 (m, 4H), 2.62-2.48 (m, 2H), 2.29-2.18 (m,6H), 2.16-2.11 (m, 3H), 1.96-1.86 (m, 2H), 1.35-1.22 (m, 2H). Purity byNMR>95%. LCMS Method 5—Tr 2.18 min (ES⁺) (M+H⁺) 437.

[Intermediate 110]—tert-Butyl3-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4,6-trimethylbenzoate

tert-Butyl 3-bromo-2,4,6-trimethylbenzoate [Intermediate 94] (80%, 200mg, 0.53 mmol), 2-(4-aminopiperidin-1-yl)benzonitrile (121 mg, 0.6mmol), NaO^(t)Bu (131 μl, 1.07 mmol), Pd₂(dba)₃ (49 mg, 0.05 mmol) and(±)-BINAP (67 mg, 0.11 mmol) were suspended in toluene (4 ml). Thereaction mixture was degassed with N₂ (g) and heated at 110° C. for 16hours. The reaction was allowed to cool to ambient temperature, filteredand concentrated in vacuo. The crude product was purified by flashcolumn chromatography, eluting with 0 to 34% TBME in heptane, to yieldthe title compound as an orange solid (144 mg, 86%). ¹H NMR (250 MHz,Chloroform-d) δ 7.55 (dd, J=7.9, 1.6 Hz, 1H), 7.50-7.40 (m, 1H),7.05-6.93 (m, 2H), 6.84 (s, 1H), 3.57 (d, J=12.6 Hz, 2H), 3.13-2.68 (m,4H), 2.34-2.15 (m, 9H), 2.06 (d, J=10.9 Hz, 2H), 1.80-1.64 (m, 2H), 1.60(s, 9H). LCMS Method 3—Tr=2.14 min (ES+) (M+H⁺) 420.2.

[Intermediate111]—3-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-2,4,6-trimethylbenzoicAcid

To a stirred solution of tert-butyl3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoate[Intermediate 110] (86%, 133 mg, 0.27 mmol) in MeOH (1 ml) was added 4MHCl in dioxane (0.4 ml). The reaction was stirred at ambient temperatureovernight and then at 50° C. for 7 hours. The reaction mixture wascooled to ambient temperature and concentrated in vacuo. The crudeproduct was dissolved in MeOH (1 ml) and loaded onto an SCX-2 cartridge(2 g). The cartridge was washed with MeOH (4×11 ml) and eluted with 2MNH₃ in MeOH (4×11 ml). The resulting fractions were concentrated invacuo to yield the title compound as a brown solid (103 mg, 90%). ¹H NMR(500 MHz, DMSO-d6) δ 7.67 (dd, J=7.7, 1.5 Hz, 1H), 7.60-7.54 (m, 1H),7.14 (d, J=8.4 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 6.76 (d, J=11.0 Hz, 1H),3.48 (d, J=12.2 Hz, 2H), 2.94-2.82 (m, 1H), 2.78 (t, J=11.8 Hz, 2H),2.20 (d, J=4.2 Hz, 3H), 2.15 (d, J=9.5 Hz, 3H), 2.12 (s, 3H), 1.86 (d,J=11.2 Hz, 2H), 1.67 (dt, J=20.4, 10.1 Hz, 2H). LCMS Method 1—Tr=1.07min (ES+) (M+H⁺) 364.1.

[Intermediate 112]—Methyl2,4,6-trimethyl-3-{[1-(pyrimidin-2-yl)piperidin-4-yl]amino}benzoate

Methyl 3-bromo-2,4,6-trimethyl-benzoate (1.13 g, 4.39 mmol),1-(pyrimidin-2-yl)piperidin-4-amine (783 mg, 4.39 mmol), NaO^(t)Bu (1.08ml, 8.79 mmol), Pd₂(dba)₃ (402 mg, 0.44 mmol) and (±)-BINAP (547 mg,0.88 mmol) were suspended in toluene (20 ml). The reaction was degassedwith N₂ (g) and then stirred at 100° C. for 18 hours. Pd₂(dba)₃ (402 mg,0.44 mmol) and (+)-BINAP (547 mg, 0.88 mmol) were added to the reactionmixture and heated for 6 hours. The reaction was filtered through celiteand the filtrate was concentrated in vacuo. The crude product waspurified by flash column chromatography, eluting with 0 to 25% EtOAc inheptane. The product containing fractions were reduced in vacuo to yieldthe title compound as an orange solid (1.21 g, 74%). ¹H NMR (250 MHz,Chloroform-d) δ 8.29 (d, J=4.7 Hz, 2H), 6.85 (s, 1H), 6.46 (t, J=4.7 Hz,1H), 4.76 (d, J=13.5 Hz, 2H), 3.90 (s, 3H), 3.11 (t, J=10.9 Hz, 1H),2.96-2.73 (m, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 1.99 (d,J=12.6 Hz, 2H), 1.51-1.17 (m, 2H). LCMS Method 1—Tr=1.14 min (ES+)(M+H⁺) 355.2

[Intermediate113]—2,4,6-trimethyl-3-{[1-(pyrimidin-2-yl)piperidin-4-yl]amino}benzoicAcid

A flask was charged with methyl2,4,6-trimethyl-3-[(1-pyrimidin-2-yl-4-piperidyl)amino]benzoate[Intermediate 112] (1.13 g, 3.19 mmol), powdered KOH (1.79 g, 31.9mmol), N-methyl-N,N-dioctyloctan-1-aminium chloride (0.73 ml, 1.59 mmol)and water (0.17 ml). The reaction mixture was stirred for 5 minutes atambient temperature. The reaction mixture was heated at 90° C. for 16hours. The reaction was re-treated with powdered KOH (3.58 g, 63.8mmol), N-methyl-N,N-dioctyloctan-1-aminium chloride (1.46 ml, 3.19 mmol)and water (0.17 ml). The reaction was then re-treated every 24 hours,for a period of 72 hours, with powdered KOH (3.58 g, 63.8 mmol),N-methyl-N,N-dioctyloctan-1-aminium chloride (1.46 ml, 3.19 mmol) andwater (1.34 ml). Re-treatments took place at ambient temperature withstirring and then the reaction was heated at 90° C. After a final 24hours heating at 90° C. the reaction was allowed to cool to ambienttemperature. The reaction was diluted with water (50 ml) and washed withEt₂O (2×30 ml). The pH of the aqueous layer was modulated to pH 3 with6M. aq. HCl. The aqueous layer was extracted with EtOAc (3×100 ml). Thecombined organics were dried over Na₂SO₄, filtered and concentrated invacuo to yield the title compound as an orange solid (300 mg, 28%). ¹HNMR (250 MHz, DMSO-d6) δ 8.33 (d, J=4.7 Hz, 2H), 6.83 (s, 1H), 6.57 (t,J=4.7 Hz, 1H), 4.63 (d, J=13.3 Hz, 2H), 3.01 (t, J=11.0 Hz, 1H), 2.85(t, J=11.6 Hz, 2H), 2.20 (s, 3H), 2.17 (s, 3H), 2.14 (s, 3H), 1.78 (d,J=10.2 Hz, 2H), 1.39 (tt, J=11.9, 6.4 Hz, 2H). LCMS Method 1—Tr=0.87 min(ES+) (M+H⁺) 341.15.

[Intermediate114]—2-{4-[(3-{3-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]piperazine-1-carbonyl}-2,4,6-trimethylphenyl)amino]piperidin-1-yl}benzonitrile

To a stirred solution of3-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4,6-trimethylbenzoic acidhydrochloride [Intermediate 111] (253 mg, 0.63 mmol) in dry DMF (2 ml)was added HATU (265 mg, 0.70 mmol) and DiPEA (221 μl, 1.27 mmol). Thereaction mixture was stirred at ambient temperature for 35 minutes. In aseparate flask,3-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4,6-trimethylbenzoic acidhydrochloride (253 mg, 0.63 mmol) and DiPEA (221 μl, 1.27 mmol) weredissolved in dry DMF (2 ml) and stirred at ambient temperature for 35minutes. After stirring each flask for 35 minutes, the two reactionmixtures were combined and stirred over the weekend. The reactionmixture was then concentrated in vacuo. The resultant residue wasdissolved in DCM (10 ml) and washed with sat aq NaHCO₃ (15 ml). Theaqueous phase was extracted with DCM (3×15 ml). The combined organicswere dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash column chromatography, eluting with 0 to3% MeOH in DCM, to yield the title compound as an orange solid (320 mg,73%). LCMS Method 6—Tr=3.51, 3.68, 3.74 min (ES+) (M+H⁺) 591.4.

[Intermediate115]—2-{4-[(3-{3-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-4-phenylpiperazine-1-carbonyl}-2,4,6-trimethylphenyl)amino]piperidin-1-yl}benzonitrile

A pressure tube was charged with2-{4-[(3-{3-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]piperazine-1-carbonyl}-2,4,6-trimethylphenyl)amino]piperidin-1-yl}benzonitrile[Intermediate 114] (320 mg, 0.54 mmol), potassium fluoride (63 mg, 1.08mmol), 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (158 μl, 0.65mmol) and dry MeCN (4 ml) under nitrogen. The reaction mixture wassealed and heated at 100° C. overnight. The reaction mixture was cooledto ambient temperature and concentrated in vacuo. The crude product waspurified by flash column chromatography, eluting with 0% to 50% EtOAc inheptane. The product containing fractions were reduced in vacuo to yieldthe title compound as a yellow solid (160 mg, 39%). LCMS Method1—Tr=1.39 min (ES+) (M+H⁺) 667.30.

[Intermediate116]—2-[4-({3-[(3S)-3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2,4,6-trimethylphenyl}amino)piperidin-1-yl]benzonitrile

3-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4,6-trimethylbenzoic acidhydrochloride [Intermediate 111] (1.39 g, 3.48 mmol) and HATU (1.45 g,3.82 mmol) were dissolved in dry DMF (15 ml). DiPEA (2.42 ml, 13.9 mmol)was added and the reaction mixture was stirred at ambient temperaturefor 20 minutes. A solution of [(2S)-1-phenylpiperazin-2-yl]methanol (668mg, 3.48 mmol) in dry DMF (5 ml) was added and the reaction mixture wasstirred at 40° C. overnight. The reaction mixture was concentrated invacuo. The resultant residue was dissolved in DCM (50 ml) and washedwith sat. aq. NaHCO₃ (50 ml). The aqueous layer was extracted with DCM(3×50 ml). The combined organics were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flash columnchromatography, eluting with 0 to 2% MeOH in DCM. The product containingfractions were reduced in vacuo to yield the title compound as a creamsolid (865 mg, 45%). ¹H NMR (500 MHz, Chloroform-d) δ 7.58-7.51 (m, 1H),7.46 (dtd, J=7.5, 5.6, 2.7 Hz, 1H), 7.31-7.26 (m, 2H), 7.02-6.84 (m,6H), 4.82-4.11 (m, 1H), 4.10-3.50 (m, 6H), 3.48-2.97 (m, 6H), 2.79-2.57(m, 2H), 2.31-2.21 (m, 6H), 2.20-2.14 (m, 3H), 2.13-1.89 (m, 2H),1.76-1.64 (m, 2H), 1.51-1.43 (m, 1H). LCMS Method 1—Tr=1.13, 1.16, 1.21min (ES+) (M+H⁺) 538.65.

[Intermediate117]—2-[4-({3-[(3S)-3-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-4-phenylpiperazine-1-carbonyl]-2,4,6-trimethylphenyl}amino)piperidin-1-yl]benzonitrile

2-[4-({3-[(3S)-3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2,4,6-trimethylphenyl}amino)piperidin-1-yl]benzonitrile[Intermediate 116] (765 mg, 1.42 mmol) was dissolved in dry THF (23 ml).The reaction mixture was cooled to 5° C. and triphenylphosphine (485 mg,1.85 mmol) and 2,3-dihydro-1H-isoindole-1,3-dione (227 mg, 1.85 mmol)were added. Dipropan-2-yl diazene-1,2-dicarboxylate (363 μl, 1.85 mmol)was added dropwise to the reaction mixture at 5° C. The reaction wasstirred at 5° C. for 2 hours and then allowed to warm to ambienttemperature over 5 hours. The reaction was acidified with 1M. aq. HCl (5ml) and extracted with EtOAc (3×20 ml). The combined organics werewashed with sat. aq. NaHCO₃ (50 ml), dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flash columnchromatography, eluting with 0 to 70% TBME in heptane. The productcontaining fractions were concentrated in vacuo to a volume of ˜300 ml.The resulting suspension was sonicated and the precipitate collected byfiltration to yield the title compound as a white solid (430 mg, 40%).LCMS Method 1—Tr=1.39 min (ES+) (M+H⁺) 667.30.

[Intermediate 118]—tert-Butyl(3S)-3-(hydroxymethyl)-4-phenylpiperazine-1-carboxylate

1-tert-Butyl 3-methyl (3S)-4-phenylpiperazine-1,3-dicarboxylate[Intermediate 117] (13.7 g, 42.76 mmol) was dissolved in dry THF (250ml). The reaction mixture was cooled to 0° C. and a solution of 2.4MLiAlH₄ in THF (35.6 ml, 85.5 mmol) was added dropwise. The reaction wasstirred at 0° C. for 30 minutes and then allowed to warm to ambienttemperature and stirred for 1 hour. The reaction mixture was cooled to0° C. and quenched with water (3.2 ml). 15% aq. NaOH (3.2 ml) and thenwater (9.6 ml) were added and the reaction mixture was allowed to warmto ambient temperature overnight. The reaction mixture was filteredthrough celite, rinsing with EtOAc. The filtrate was concentrated invacuo to yield the title compound as a white solid (11.6 g, 92%). ¹H NMR(500 MHz, Chloroform-d) δ 7.34-7.22 (m, 2H), 6.91 (d, J=7.9 Hz, 2H),6.85 (t, J=7.2 Hz, 1H), 4.36-4.06 (m, 1H), 3.98 (d, J=10.8 Hz, 1H),3.94-3.76 (m, 1H), 3.69-3.47 (m, 2H), 3.41-3.02 (m, 4H), 1.49 (s, 9H).LCMS Method 1—Tr=1.11 min (ES+) (M+H⁺) 293.05.

[Intermediate 119]—[(2S)-1-Phenylpiperazin-2-yl]methanol

tert-Butyl (3S)-3-(hydroxymethyl)-4-phenylpiperazine-1-carboxylate[Intermediate 118] (11.6 g, 39.7 mmol) was dissolved in EtOH (110 ml).The reaction mixture was cooled to 0° C. and 4M HCl in dioxane (40 ml)was added dropwise. The reaction mixture was stirred at ambienttemperature overnight. 4M HCl in dioxane (20 ml) was added and thereaction mixture was stirred for at ambient temperature for 4 hours. Thereaction was concentrated in vacuo. The resultant residue was dissolvedin (1:1) MeOH/DCM and loaded onto MP-TsOH (77 g, 240 mmol) resin. Theresin solution was left to stand for 30 min, the resin was filtered,washed sequentially with DCM (50 ml), MeOH (50 ml), DCM (50 ml) and MeOH(50 ml). The product was eluted with 2M NH₃ in MeOH, the eluent wasconcentrated in vacuo. The resultant residue was purified by flashcolumn chromatography (KP-NH) eluting with a gradient from 0% to 5% MeOHin DCM. The product containing fractions were concentrated in vacuo. Theresultant residue was purified by flash column chromatography (KP-SIL)eluting with a gradient from 20% to 100% ‘2M NH₃ in MeOH’ in DCM. Theproduct containing fractions were concentrated in vacuo to afford thetitle compound as a white solid (4.7 g, 61%). With a chiral purity 78%ee. ¹H NMR (500 MHz, Chloroform-d) δ 7.29-7.24 (m, 2H), 6.92 (d, J=7.9Hz, 2H), 6.84 (t, J=7.3 Hz, 1H), 3.95 (ddd, J=11.0, 4.4, 1.2 Hz, 1H),3.86-3.74 (m, 2H), 3.45 (td, J=11.5, 3.7 Hz, 1H), 3.41-3.27 (m, 2H),3.24-3.11 (m, 2H), 3.00 (td, J=11.3, 3.8 Hz, 1H). LCMS Method 1—Tr=0.38min (ES+) (M+H⁺) 192.95.

[Intermediate 120]—tert-Butyl(3S)-3-{[(tert-butyldimethylsilyl)oxy]methyl}piperazine-1-carboxylate

To a stirred solution of tert-butyl(3S)-3-(hydroxymethyl)piperazine-1-carboxylate (5.0 g, 23.1 mmol) andimidazole (2.36 g, 34.7 mmol) in DCM (25 ml) was addedtert-butyl(chloro)dimethylsilane (3.59 g, 23.8 mmol). The reaction wasstirred at ambient temperature for 72 hours. The reaction mixture wasdiluted with sat. aq. NaHCO₃(50 ml) and the organic layer separated. Theaqueous layer was extracted with DCM (2×30 ml), the combined organicswere dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash column chromatography, with a gradientfrom 10% to 100% EtOAc in heptane. The product contain fractions werecombined and reduced in vacuo to yield the title compound as a yellowoil (7.0 g, 92% yield). ¹H NMR (250 MHz, Chloroform-d) δ 3.85 (d, J=11.9Hz, 2H), 3.53 (dd, J=9.8, 4.3 Hz, 1H), 3.41 (dd, J=9.8, 7.0 Hz, 1H),3.00-2.86 (m, 1H), 2.85-2.57 (m, 3H), 2.57-2.36 (m, 1H), 1.40 (s, 9H),0.84 (s, 9H), 0.00 (s, 6H). LCMS Method 1 [ELS]—Tr=0.92 min (ES+) (M+H⁺)331.25.

[Intermediate 121]—tert-butyl(3S)-3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-(pyridin-2-yl)piperazine-1-carboxylate

A pressure tube was charged with tert-butyl(3S)-3-{[(tert-butyldimethylsilyl)oxy]methyl}piperazine-1-carboxylate[Intermediate 120] (1.0 g, 3.03 mmol), 2-bromopyridine (0.41 ml, 4.24mmol), RuPhos Pd G3 (253 mg, 0.30 mmol), ^(t)BuONa (582 mg, 6.05 mmol),1,4-dioxane (10 ml) and ^(t)BuOH (5 ml). The reaction was degassed withN₂. The tube was sealed and the reaction was stirred at 110° C. for 16hours. The reaction was cooled to ambient temperature and water (60 ml)was added. The mixture was extracted with DCM (3×60 ml), the combinedorganics were dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by flash column chromatography, eluting witha gradient of 0% to 7% EtOAc in heptane. The product containing fractionwere combined and reduced in vacuo to yield the title compound as ayellow oil (840 mg, 68%). ¹H NMR (250 MHz, Chloroform-d) δ 8.25-8.05 (m,1H), 7.46 (ddd, J=8.8, 7.2, 2.0 Hz, 1H), 6.72-6.48 (m, 2H), 4.37-4.15(m, 2H), 4.14-3.81 (m, 2H), 3.77-3.47 (m, 2H), 3.32-2.82 (m, 3H), 1.48(s, 9H), 0.85 (s, 9H), 0.02 (s, 6H). LCMS Method 1—Tr=1.24 min (ES+)(M+H⁺) 408.05.

[Intermediate 122]—[(2S)-1-(Pyridin-2-yl)piperazin-2-yl]methanol]

tert-Butyl(3S)-3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-(pyridin-2-yl)piperazine-1-carboxylate[Intermediate 121] (840 mg, 2.06 mmol) was dissolved in MeOH (2 ml) and5.15 ml) was added. The reaction was stirred for 16 hours at ambienttemperature. The reaction was concentrated and the resultant residue wasdissolved in the minimum volume of (1:1) MeOH/DCM and loaded onto anSCX-2 cartridge (10 g). The cartridge was washed sequentially with MeOH(30 ml), DCM, (30 ml), MeOH (30 ml), DCM, (30 ml) and MeOH (30 ml). Theproduct was eluted with 7M NH₃ in MeOH (60 ml). The resulting fractionswere concentrated in vacuo to yield the title compound as a colourlessoil (424 mg, 100%). ¹H NMR (250 MHz, Chloroform-d) δ 8.19-8.03 (m, 1H),7.48 (ddd, J=8.9, 7.1, 2.0 Hz, 1H), 6.71-6.54 (m, 2H), 4.52 (d, J=3.5Hz, 1H), 4.05 (dd, J=11.0, 5.2 Hz, 1H), 4.00-3.91 (m, 1H), 3.91-3.78 (m,1H), 3.56-3.38 (m, 1H), 3.38-3.29 (m, 1H), 3.17 (dt, J=11.5, 1.8 Hz,1H), 3.07 (dd, J=12.3, 4.5 Hz, 1H), 2.93 (td, J=11.8, 3.9 Hz, 1H). LCMSMethod 1 [ELS]—Tr=0.19 min (ES+) (M+H⁺) 194.30.

[Intermediate 123]—tert-Butyl(3S)-3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-(5-fluoropyridin-2-yl)piperazine-1-carboxylate

A pressure tube was charged with tert-butyl(3S)-3-{[(tert-butyldimethylsilyl)oxy] methyl}piperazine-1-carboxylate[Intermediate 120] (0.90 g, 2.72 mmol), 2-bromo-5-fluoropyridine (0.39ml, 3.81 mmol), RuPhos Pd G3 (228 mg, 0.27 mmol), ^(t)BuONa (523 mg,5.45 mmol), dioxane (9 ml) and ^(t)BuOH (4.5 ml). The reaction wasde-gassed with N₂ and the tube sealed. The reaction was heated at 110°C. for 16 hours. Water (60 ml) was added and the suspension wasfiltered. The filtrate was extracted with DCM (3×60 ml). The combinedorganic were dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by flash column chromatography, eluting witha gradient of 0% to 7% EtOAc in heptane, to give the title compound as ayellow oil (0.91 g, 79%). ¹H NMR (500 MHz, Chloroform-d) δ 8.02 (d,J=3.0 Hz, 1H), 7.26-7.20 (m, 1H), 6.57 (d, J=7.9 Hz, 1H), 4.28-4.15 (m,2H), 4.14-3.80 (m, 2H), 3.67 (t, J=9.2 Hz, 1H), 3.57 (s, 1H), 3.19-2.93(m, 3H), 1.48 (s, 9H), 0.84 (s, 9H), 0.01 (s, 6H). LCMS Method 1—Tr=1.62min (ES+) (M+H⁺) 426.2

[Intermediate 124]—[(2S)-1-(5-Fluoropyridin-2-yl)piperazin-2-yl]methanol

tert-Butyl (3S)-3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-(5-fluoropyridin-2-yl)piperazine-1-carboxylate[Intermediate 123] (1.0 g, 2.37 mmol) was dissolved in MeOH (2 ml). 4MHCl in dioxane (5.93 ml) was added and the reaction mixture was stirredfor 16 hours at ambient temperature. The reaction was concentrated invacuo. The resultant residue was dissolved in the minimum volume of(1:1) MeOH/DCM and loaded onto an SCX-2 cartridge (10 g). The cartridgewas washed sequentially with MeOH (30 ml), DCM, (30 ml), MeOH (30 ml),DCM, (30 ml) and MeOH (30 ml). The product was eluted with 7M NH₃ inMeOH (60 ml). The resulting fractions were concentrated in vacuo toyield the title compound as a colourless oil (416 mg, 83%). ¹H NMR (250MHz, Chloroform-d) δ 8.01 (d, J=3.1 Hz, 1H), 7.36-7.15 (m, 1H), 6.58(dd, J=9.3, 3.3 Hz, 1H), 4.39 (dd, J=4.2, 1.8 Hz, 1H), 4.06-3.88 (m,2H), 3.74 (ddd, J=12.3, 3.8, 1.9 Hz, 1H), 3.44 (td, J=12.1, 3.8 Hz, 1H),3.33 (dt, J=11.8, 1.7 Hz, 1H), 3.21-3.11 (m, 1H), 3.07 (ddd, J=11.8,4.0, 0.9 Hz, 1H), 2.92 (td, J=11.7, 3.9 Hz, 1H). LCMS Method 1[ELS]—Tr=0.26 min (ES+) (M+H⁺) 212.1.

[Intermediate 125]—2-(benzylamino)-N-(3,4-difluorophenyl)acetamide

To a stirred solution of 2-chloro-N-(3,4-difluorophenyl)acetamide (2.92ml, 0.02 mol) in THF (42 ml) was added 1-phenylmethanamine (8.29 ml,0.08 mol). The reaction was heated at 80° C. for 16 hours. The reactionwas cooled to ambient temperature and filtered. The filtrate wasconcentrated in vacuo. The crude product was purified twice via reversephase column chromatography [C18], using a gradient of 0% to 100% MeCN(with 0.1% NH₃ modifier) in water (with 0.1% NH₃ modifier), to give thetitle compound as a white solid (4.2 g, 82%). ¹H NMR (500 MHz,Chloroform-d) δ 9.31 (s, 1H), 7.71-7.63 (m, 1H), 7.42-7.36 (m, 2H),7.36-7.30 (m, 3H), 7.16-7.06 (m, 2H), 3.87 (s, 2H), 3.45 (s, 2H). LCMSMethod 1—Tr=0.83 min (ES+) (M+H⁺) 277.1.

[Intermediate126]—2-{Benzyl[(2R)-3-chloro-2-hydroxypropyl]amino}-N-(3,4-difluorophenyl)acetamide

A flask was charged with 2-(benzylamino)-N-(3,4-difluorophenyl)acetamide[Intermediate 125] (3.9 g, 14.1 mmol), dry MeOH (62 ml), oven driedMgSO₄ (2.07 g, 17.2 mmol), dry DCM (21 ml) and(2R)-2-(chloromethyl)oxirane (2.77 ml, 0.04 mol). The reaction wasstirred at 35° C. for 24 hours and stirred at ambient temperature overthe weekend. The reaction was filtered through celite, rinsing withEtOAc. The filtrate was concentrated in vacuo to yield the titlecompound as a yellow oil (5.25 g, 96%). LCMS Method 1—Tr=1.05 min (ES+)(M+H⁺) 369.0, 371.1.

[Intermediate127]—(6S)-4-Benzyl-1-(3,4-difluorophenyl)-6-(hydroxymethyl)piperazin-2-one

2-{benzyl[(2R)-3-chloro-2-hydroxypropyl]amino}-N-(3,4-difluorophenyl)acetamide[Intermediate 126] (5.2 g, 14.0 mmol) was dissolved in (1:1) MeOH/THF(155 ml). 1.25M aq. NaOH (77.6 ml, 97.0 mmol) was added dropwise and thereaction mixture stirred at ambient temperature for 1 hour. The reactionmixture was diluted with sat. aq. brine (130 ml) and extracted withEtOAc (3×150 ml). The combined organics were washed with sat. aq. brine(130 ml), dried over Na₂SO₄, filtered and concentrated in vacuo to yieldthe title compound as a colourless oil (4.54 g, 92%). ¹H NMR (500 MHz,Chloroform-d) δ 7.40-7.36 (m, 2H), 7.35-7.29 (m, 3H), 7.24-7.13 (m, 2H),7.06-7.01 (m, 1H), 4.50 (s, 1H), 3.72-3.56 (m, 6H), 3.27 (d, J=11.7 Hz,1H), 3.02 (d, J=16.7 Hz, 1H), 2.94-2.84 (m, 1H). LCMS Method 1—Tr=0.88min (ES+) (M+H⁺) 333.00.

[Intermediate128]—(6S)-1-(3,4-Difluorophenyl)-6-(hydroxymethyl)piperazin-2-one

The H-Cube (Continuous Flow Hydrogenation Reactor) was loaded with a 20%Pd(OH)₂ cartridge. A solution of(6S)-4-benzyl-1-(3,4-difluorophenyl)-6-(hydroxymethyl)piperazin-2-one[Intermediate 127] (250 mg, 0.75 mmol) in MeOH (15 ml) was passedthrough the system twice at with a flow rate of 0.6 ml/min at 60° C.with pressure of 20 bar. The reaction mixture was concentrated in vacuoto yield the title compound as a colourless oil (123 mg, 65%). ¹H NMR(500 MHz, Chloroform-d) δ 7.25-7.14 (m, 2H), 7.05 (ddt, J=8.4, 4.0, 2.2Hz, 1H), 3.79 (dd, J=17.0, 1.4 Hz, 1H), 3.76 (dd, J=11.6, 1.4 Hz, 1H),3.72-3.64 (m, 2H), 3.63 (dt, J=3.7, 1.8 Hz, 1H), 3.52 (dd, J=12.2, 1.6Hz, 1H), 3.40 (ddd, J=12.2, 3.8, 2.1 Hz, 1H). LCMS Method I[ELS]—Tr=0.29 min (ES+) (M+H⁺) 243.0.

[Intermediate 129]—3,5-Dibromo-2,4,6-trimethylpyridine

To a solution of 2,4,6-trimethylpyridine (13.1 ml, 99.0 mmol) in TFA (60ml) was added conc. H₂SO₄ (79 ml, 1485 mmol) and NBS (88.1 g, 495 mmol).The resultant reaction was stirred at 50° C. for 25 hours, thenadditional NBS (17.6 g, 99.0 mmol) was added and the reaction stirredfor a further 5 hours at 50° C. The mixture was poured onto crushed ice(1 dm³) and the solution was basified to pH 8-9 with 50% aq. NaOH. Thesuspension was filtered and washed with water (200 ml), then the solidobtained was dried via vacuum oven overnight to afford the titlecompound as a white solid (22.1 g, 67%)

1H NMR (250 MHz, Chloroform-d) δ 2.61 (s, 6H), 2.60 (s, 3H)

LCMS Method 1—Tr=1.34 min, (ES+) (M+H⁺) 277.9, 279.9

[Intermediate 130]—tert-Butyl5-bromo-2,4,6-trimethylpyridine-3-carboxylate

To a solution of 3,5-dibromo-2,4,6-trimethylpyridine [Intermediate 129](84%, 4 g, 12.0 mmol) in Et₂O (100 ml) was slowly added 2.5M n-BuLi inhexane (6.7 ml) at −78° C. and the reaction was stirred for 1.5 hours at−78° C. Di-tert-butyl dicarbonate (3.68 g, 16.9 mmol) was then added tothe reaction and the mixture was stirred at −78° C. for 1.5 hr. Thereaction was quenched with 10% aq. citric acid solution (120 ml) and wasextracted with EtOAc (120 ml). The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to afford thetitle compound as a straw-coloured oil (3.88 g, 95%). ¹H NMR (250 MHz,Chloroform-d) δ 2.65 (s, 3H), 2.46 (s, 3H), 2.38 (s, 3H), 1.60 (s, 9H).LCMS Method 1—Tr=1.34 min, (ES+) (M+H⁺) 300.0, 302.0

[Intermediate 131]—tert-Butyl5-{[1-(2-cyano-6-fluorophenyl)piperidin-4-yl]amino}-2,4,6-trimethylpyridine-3-carboxylate

tert-Butyl 5-bromo-2,4,6-trimethylpyridine-3-carboxylate [Intermediate130] (250 mg, 0.83 mmol), 3-fluoro-2-(piperazin-1-yl)benzonitrile[Intermediate 104] (171 mg, 0.83 mmol), NaO^(t)Bu (160 mg, 1.67 mmol),(±)-BINAP (104 mg, 0.17 mmol) and Pd₂(dba)₃ (76 mg, 0.08 mmol) weresuspended in toluene (5 ml) and the mixture was de-gassed with nitrogenfor 5 min. The mixture was then sealed under a nitrogen atmosphere andstirred at 110° C. for 16 hours. The reaction was cooled to ambienttemperature and partitioned between water (15 ml) and EtOAc (15 ml). Theaqueous layer was extracted with EtOAc (2×15 ml). The combined organicswere washed with brine (25 ml), dried over Na₂SO₄ and concentrated invacuo. The crude material was purified by flash column chromatographyusing a gradient of 20% to 100% EtOAc in heptane. The product containingfractions were combined and concentrated in vacuo to afford the titlecompound as a white solid (249 mg, 57%). ¹H NMR (500 MHz, Chloroform-d)δ 7.38-7.31 (m, 1H), 7.21 (ddd, J=12.2, 8.2, 1.4 Hz, 1H), 7.06-6.99 (m,1H), 3.39 (d, J=12.3 Hz, 2H), 3.17 (t, J=12.1 Hz, 2H), 3.05-2.93 (m,1H), 2.50 (s, 3H), 2.46 (s, 3H), 2.25 (s, 3H), 2.01 (d, J=10.2 Hz, 2H),1.75-1.56 (m, 11H). LCMS Method 1—Tr=1.16 min, (ES+) (M+H⁺) 439.2.

[Intermediate132]—5-{[1-(2-Cyano-6-fluorophenyl)piperidin-4-yl]amino}-2,4,6-trimethylpyridine-3-carboxylicacid; bis TFA salt

tert-Butyl5-{[1-(2-cyano-6-fluorophenyl)piperidin-4-yl]amino}-2,4,6-trimethylpyridine-3-carboxylate[Intermediate 131] (249 mg, 0.57 mmol) was dissolved in DCM (0.5 ml) andTFA (0.5 ml, 6.53 mmol) was added. The mixture was stirred at ambienttemperature for 16 hours, then the mixture was concentrated in vacuo andthe product dried via vacuum oven to afford the title compound as awhite solid (340 mg, 77%). ¹H NMR (500 MHz, Chloroform-d) δ 7.37 (d,J=7.7 Hz, 1H), 7.28-7.20 (m, 1H), 7.12-7.04 (m, 1H), 3.39 (d, J=12.6 Hz,2H), 3.29-3.11 (m, 3H), 2.71 (s, 3H), 2.66 (s, 3H), 2.50 (s, 3H), 2.01(d, J=10.0 Hz, 2H), 1.85-1.66 (m, 2H). LCMS Method 1—Tr=0.93 min, (ES+)(M+H⁺) 383.2.

[Intermediate 133]—tert-Butyl5-{[1-(2-cyano-4-fluorophenyl)piperidin-4-yl]amino}-2,4,6-trimethylpyridine-3-carboxylate

Prepared analogously to the method for [Intermediate 131] usingtert-butyl 5-bromo-2,4,6-trimethylpyridine-3-carboxylate [Intermediate130] (250 mg, 0.83 mmol) and 5-fluoro-2-(piperazin-1-yl)benzonitrile[Intermediate 97] (171 mg, 0.83 mmol) to afford the title compound as awhite solid (242 mg, 63%). ¹H NMR (500 MHz, Chloroform-d) δ 7.29-7.26(m, 1H), 7.20 (ddd, J=9.0, 7.8, 3.0 Hz, 1H), 6.98 (dd, J=9.1, 4.6 Hz,1H), 3.46 (d, J=12.4 Hz, 2H), 3.04-2.92 (m, 1H), 2.92-2.68 (m, 3H), 2.50(s, 3H), 2.46 (s, 3H), 2.25 (s, 3H), 2.05 (d, J=12.3 Hz, 2H), 1.80-1.66(m, 2H), 1.61 (s, 9H). LCMS Method 1—Tr=1.15 min, (ES+) (M+H⁺) 429.2.

[Intermediate134]—5-{[1-(2-Cyano-4-fluorophenyl)piperidin-4-yl]amino}-2,4,6-trimethylpyridine-3-carboxylicacid; bis-TFA salt

Prepared analogously to the method for [Intermediate 132] usingtert-butyl5-{[1-(2-cyano-4-fluorophenyl)piperidin-4-yl]amino}-2,4,6-trimethylpyridine-3-carboxylate[Intermediate 133] (242 mg, 0.55 mmol) to afford the title compound as awhite solid (324 mg, 92%). ¹H NMR (500 MHz, Chloroform-d) δ 7.31 (dd,J=7.7, 3.0 Hz, 1H), 7.25 (ddd, J=8.9, 7.9, 3.0 Hz, 1H), 7.03 (dd, J=9.1,4.5 Hz, 1H), 3.49 (d, J=12.3 Hz, 2H), 3.26-3.10 (m, 1H), 2.83 (t, J=11.2Hz, 2H), 2.73 (s, 3H), 2.68 (s, 3H), 2.51 (s, 3H), 2.08 (d, J=10.1 Hz,2H), 1.89-1.73 (m, 2H). LCMS Method 1—Tr=0.92 min, (ES+) (M+H⁺) 383.2.

[Intermediate 135]—tert-Butyl2,4,6-trimethyl-5-{[1-(pyridin-2-yl)piperidin-4-yl]amino}pyridine-3-carboxylate

tert-Butyl 5-bromo-2,4,6-trimethylpyridine-3-carboxylate [Intermediate130] (89%, 300 mg, 0.89 mmol), 1-(pyridin-2-yl)piperidin-4-amine (158mg, 0.89 mmol), Pd₂(dba)₃ (81 mg, 0.09 mmol), (+)-BINAP (111 mg, 0.18mmol) and NaO^(t)Bu (171 mg, 1.78 mmol) were suspended in anhydroustoluene (5 ml) and stirred at 100° C. under nitrogen atmosphere for 20hours. The reaction was filtered and the cake was washed through withDCM. The filtrate was concentrated in vacuo and the residue obtained waspurified via reverse phase flash column chromatography [C18] using agradient of 5% to 100% acetonitrile (+0.1% NH₃ modifier) in water (+0.1%NH₃ modifier). The product containing fractions were combined andconcentrated in vacuo to afford the title compound as a straw colouredoil (183 mg, 48%). ¹H NMR (250 MHz, Chloroform-d) δ 8.24-8.13 (m, 1H),7.52-7.43 (m, 1H), 6.67 (d, J=8.6 Hz, 1H), 6.64-6.57 (m, 1H), 4.39-4.25(m, 2H), 3.17-3.00 (m, 1H), 2.91-2.77 (m, 2H), 2.49 (s, 3H), 2.47 (s,3H), 2.25 (s, 3H), 2.06-1.95 (m, 2H), 1.62 (s, 9H), 1.55-1.37 (m, 2H).LCMS Method 1—Tr=0.81 min, (ES+) (M+H⁺) 182.8.

[Intermediate136]—2,4,6-trimethyl-5-{[1-(pyridin-2-yl)piperidin-4-yl]amino}pyridine-3-carboxylicAcid; tris-TFA

tert-Butyl2,4,6-trimethyl-5-{[1-(pyridin-2-yl)piperidin-4-yl]amino}pyridine-3-carboxylate[Intermediate 135] (92%, 183 mg, 0.42 mmol) was suspended in TFA (1.63ml, 21.2 mmol) and stirred at ambient temperature for 20 hours. Thereaction mixture was concentrated in vacuo to afford the title compoundas a yellow gum (320 mg, 88%). ¹H NMR (250 MHz, MeOH-d4) δ 8.10-8.00 (m,1H), 8.00-7.93 (m, 1H), 7.49-7.40 (m, 1H), 7.04-6.94 (m, 1H), 4.33-4.16(m, 2H), 3.52-3.42 (m, 1H), 3.41-3.27 (m, 2H), 2.74 (s, 3H), 2.68 (s,3H), 2.56 (s, 3H), 2.20-2.06 (m, 2H), 1.87-1.68 (m, 2H). LCMS Method1—Tr=0.21 min, (ES+) (M+H⁺) 341.2

[Intermediate 137]—tert-Butyl5-{[1-(3-chloropyridin-2-yl)piperidin-4-yl]amino}-2,4,6-trimethylpyridine-3-carboxylate

Prepared analogously to the method for [Intermediate 135] usingtert-butyl 5-bromo-2,4,6-trimethylpyridine-3-carboxylate [Intermediate130] (89%, 170 mg, 0.50 mmol) and1-(3-chloropyridin-2-yl)piperidin-4-amine hydrochloride (125 mg, 0.50mmol) to afford the title compound as a straw-coloured oil (89 mg, 30%).¹H NMR (250 MHz, Chloroform-d) δ 8.16 (dd, J=4.8, 1.6 Hz, 1H), 7.57 (dd,J=7.7, 1.7 Hz, 1H), 6.82 (dd, J=7.7, 4.8 Hz, 1H), 3.90-3.73 (m, 2H),3.10-2.94 (m, 1H), 2.90-2.73 (m, 2H), 2.50 (s, 3H), 2.45 (s, 3H), 2.25(s, 3H), 2.07-1.95 (m, 2H), 1.71-1.53 (m, 11H). LCMS Method 1—(2 min,low pH) Tr=1.06 min, (ES+) (M+H⁺) 431.2.

[Intermediate138]—5-{[1-(3-Chloropyridin-2-yl)piperidin-4-yl]amino}-2,4,6-trimethylpyridine-3-carboxylicacid; tris-TFA salt

Prepared analogously to the method for [Intermediate 136] usingtert-butyl5-{[1-(3-chloropyridin-2-yl)piperidin-4-yl]amino}-2,4,6-trimethylpyridine-3-carboxylate[Intermediate 137] (68.4%, 183 mg, 0.29 mmol) to afford the titlecompound as a yellow gum (304 mg, 100%). ¹H NMR (250 MHz, MeOH-d4) δ8.14 (dd, J=5.0, 1.6 Hz, 1H), 7.79 (dd, J=7.8, 1.6 Hz, 1H), 6.98 (dd,J=7.8, 5.0 Hz, 1H), 3.94-3.78 (m, 2H), 3.28-3.16 (m, 1H), 3.00-2.86 (m,2H), 2.72 (s, 3H), 2.65 (s, 3H), 2.55 (s, 3H), 2.09-1.96 (m, 2H),1.93-1.73 (m, 2H). LCMS Method 1—Tr=0.80 min, (ES+) (M+H⁺) 375.1

[Intermediate 139]—(2R or 2S)-1-phenylpiperazine-2-carboxamide

The title compound was afforded from chiral separation of1-Phenylpiperazine-2-carboxamide hydrochloride [Intermediate 50].

[Intermediate 140]—tert-butyl2,4,6-trimethyl-3-{[1-(pyridin-2-yl)piperidin-4-yl]amino}benzoate

Prepared analogously to [Intermediate 95] from tert-butyl3-bromo-2,4,6-trimethyl-benzoate [Intermediate 94] (500 mg, 1.67 mmol)and 1-(pyridin-2-yl)piperidin-4-amine (296 mg, 1.67 mmol) to yield thetitle compound as a brown oil (391 mg, 53%). 1H NMR (500 MHz, DMSO-d6) δ8.11-8.05 (m, 1H), 7.49 (ddd, J=8.9, 7.1, 2.0 Hz, 1H), 6.81 (t, J=4.3Hz, 2H), 6.57 (dd, J=7.0, 4.9 Hz, 1H), 4.27 (d, J=13.2 Hz, 2H), 3.64 (d,J=10.4 Hz, 1H), 3.01-2.88 (m, 1H), 2.77 (t, J=11.7 Hz, 2H), 2.19 (s,3H), 2.14 (s, 3H), 2.12 (s, 3H), 1.76 (d, J=10.4 Hz, 2H), 1.53 (s, 9H),1.42 (qd, J=12.4, 4.0 Hz, 2H) LCMS Method 1—Tr=1.05 min (ES+) (M+H⁺)396.2

[Intermediate1411]—2,4,6-trimethyl-3-{[1-(pyridin-2-yl)piperidin-4-yl]amino}benzoicacid

Prepared analogously to [Intermediate 100] from tert-butyl2,4,6-trimethyl-3-{[1-(pyridin-2-yl)piperidin-4-yl]amino}benzoate[Intermediate 140] (90%, 391 mg, 0.89 mmol) to yield the title compoundas a pale yellow powdery solid (299 mg, 94%).

H NMR (500 MHz, DMSO-d6) δ 8.12-8.06 (m, 1H), 7.49 (ddd, J=8.9, 7.1, 2.0Hz, 1H), 6.82 (d, J=8.7 Hz, 1H), 6.74 (s, 1H), 6.58 (dd, J=7.0, 4.9 Hz,1H), 4.27 (d, J=13.2 Hz, 2H), 2.99-2.90 (m, 1H), 2.77 (t, J=11.6 Hz,2H), 2.17 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.78 (d, J=10.3 Hz, 2H),1.41 (qd, J=12.4, 4.0 Hz, 2H)

LCMS Method 1—Tr=0.69 min (ES+) (M+H⁺) 340.1

[Intermediate 142]—1,3-Difluoro-2-methanesulfinylbenzene

To a stirred solution of 1,3-difluoro-2-(methylsulfanyl)benzene (25 g,156 mmol) in THF (250 ml) at 0° C. was added a solution of m-CPBA (75%,37.7 g, 164 mmol) in THF (250 ml) dropwise while maintaining theinternal reaction temperature at <10° C. Then the reaction was stirredfor 1 hour while allowing it to warm to room temperature. The reactionwas stirred overnight at room temperature and then concentrated invacuo. The residue was diluted with DCM (500 ml) and 2M aq. NaOH (500ml). The phases were separated and the aqueous layer was extracted with(2×500 ml). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound as ayellow oil (5.5 g, 75%).

1H NMR (250 MHz, Chloroform-d) δ 7.48 (tt, J=8.3, 6.2 Hz, 1H), 7.01 (t,J=8.3 Hz, 2H), 3.11 (s, 3H).

LCMS Method 1—Tr=0.64 min (ES+) (M+H⁺) 176.8

[Intermediate 143]—tert-ButylN-[(2,6-difluorophenyl)(methyl)oxo-lambda6-sulfanylidene]carbamate

To a stirred solution of 1,3-difluoro-2-methanesulfinylbenzene[Intermediate 142] (26.4 g, 150 mmol) in DCM (406 ml) was addedtert-butyl carbamate (35.1 g, 300 mmol) in DCM (406 ml), magnesium(2+)ion oxidandiide (24.2 g, 599 mmol), rhodium(2+) acetate (1:2) (1.99 g,4.49 mmol) and bis(acetyloxy)(phenyl)-lambda˜3˜-iodane (96.5 g, 300mmol). The reaction was flushed with N₂ and the suspension was stirredat room temperature for 66 hours. Celite was added to the reaction. Thereaction was filtered and the filtrate was concentrated in vacuo. Theresidue was mobilised in the minimum volume of DCM, filtered and thefiltrate was concentrated (×2). The crude product was purified by flashcolumn chromatography using a gradient of 0% to 100% EtOAc in heptane.The product containing fractions were combined and concentrated in vacuoto afford the title compound as a pale yellow oil (7.9 g, 16%).

1H NMR (250 MHz, Chloroform-d) δ 7.60 (tt, J=8.4, 5.9 Hz, 1H), 7.08 (t,J=8.7 Hz, 2H), 3.41 (s, 3H), 1.40 (s, 9H).

LCMS Method 1—Tr=1.01 min (ES+) (M+H)+ 237.0

[Intermediate 144]—tert-Butyl4-[2-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-lambda6-sulfanyl)-3-fluorophenyl]piperazine-1-carboxylate

To a stirred solution of tert-butyl piperazine-1-carboxylate (1.24 g,6.63 mmol) and tert-butylN-[(2,6-difluorophenyl)(methyl)oxo-lambda6-sulfanylidene]carbamate[Intermediate 143] (84%, 2 g, 5.77 mmol) in PhMe (20 ml) was addedCs₂CO₃ (2.25 g, 6.92 mmol). The reaction was heated at 115° C. for 1hour. The reaction was allowed to cool to room temperature and wasdiluted with water (20 ml). The layers were separated and the aqueouslayer was extracted with DCM (2×20 ml). The combined organic extractswere dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified via reverse phase column chromatography [C18],using a gradient of 0 to 100% MeCN (with 0.1% ammonia modifier) in water(with 0.1% ammonia modifier), to give the title compound as a whitesolid (1.71 g, 65%).

1H NMR (250 MHz, Chloroform-d) δ 7.55 (td, J=8.2, 5.8 Hz, 1H), 7.10 (d,J=8.2 Hz, 1H), 7.01 (ddd, J=11.0, 8.3, 1.0 Hz, 1H), 4.38-2.57 (m, 11H),1.47 (s, 9H), 1.44 (s, 9H).

LCMS Method 1—Tr=1.19 min (ES+) (M+H)+ 458.1

[Intermediate145]—2-fluoro-6-(piperazin-1-yl)phenyl](imino)methyl-lambda6-sulfanone

To a stirred solution of tert-butyl4-[2-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-lambda6-sulfanyl)-3-fluorophenyl]piperazine-1-carboxylate[Intermediate 144] (25.8 g, 56.4 mmol) in DCM (194 ml) was added TFA(64.7 ml, 846 mmol). The reaction was stirred at room temperature for 18hours and was then concentrated in vacuo. The residue was dissolved inthe minimum volume of (1:1) MeOH/DCM. A glass column was charged withMP-TsOH (109 g, 338 mmol) and the resin was washed with DCM (300 ml),MeOH (300 ml), DCM (300 ml) and MeOH (300 ml). The solution of crudeproduct was loaded under gravity. When fully absorbed, the resin wasleft for 5 minutes and then the resin was washed with DCM (500 ml), MeOH(500 ml), DCM (500 ml) and MeOH (500 ml). The product was eluted with3.5M NH₃ in MeOH (1.5 1). The resulting fractions were concentrated invacuo to give the title compound as a beige solid (13.7 g, 93%).

1H NMR (500 MHz, Chloroform-d) δ 7.44 (td, J=8.2, 6.2 Hz, 1H), 7.17 (d,J=8.1 Hz, 1H), 6.99 (ddd, J=10.7, 8.4, 1.0 Hz, 1H), 5.52 (s, 1H), 3.42(d, J=5.5 Hz, 3H), 3.34 (s, 1H), 3.20-2.94 (m, 6H), 2.78 (s, 1H).

LCMS Method 6—Tr=1.56 min (ES+) (M+H)+ 257.9

[Intermediate 146]—(R orS)-[2-fluoro-6-(piperazin-1-yl)phenyl](imino)methyl-lambda6-sulfanone[Intermediate 147]—(S orR)-[2-fluoro-6-(piperazin-1-yl)phenyl](imino)methyl-lambda6-sulfanone

2-Fluoro-6-(piperazin-1-yl)phenyl](imino)methyl-lambda6-sulfanone (9.8g, 38.08 mmol) was dissolved to 100 mg/ml in MeOH and was then purifiedby SFC on a Lux C4 column (21.2 mm×250 mm, 5 μm) eluting with 45:55MeOH:CO₂ (containing 0.1% v/v NH₃). The product containing fractionswere combined and concentrated in vacuo to afford the title compounds aswhite solids (4.77 g, 49%, with a chiral purity 99% ee and 4.86 g, 49%,with a chiral purity 98% ee respectively). 1H NMR (500 MHz,Chloroform-d) δ 7.44 (td, J=8.2, 6.2 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H),6.99 (ddd, J=10.7, 8.3, 1.0 Hz, 1H), 5.52 (s, 1H), 3.43 (d, J=5.5 Hz,3H), 3.35 (s, 1H), 3.20-2.88 (m, 6H), 2.78 (s, 1H).

LCMS Method 6—Tr=1.59 min (ES+) (M+H)+ 258.0

¹H NMR (500 MHz, Chloroform-d) δ 7.44 (td, J=8.2, 6.2 Hz, 1H), 7.18 (d,J=8.1 Hz, 1H), 7.00 (ddd, J=10.7, 8.3, 1.0 Hz, 1H), 5.45 (s, 1H), 3.43(d, J=5.5 Hz, 3H), 3.35 (s, 1H), 3.25-2.95 (m, 6H), 2.81 (s, 1H).

LCMS Method 6—Tr=1.59 min (ES+) (M+H)+ 258.0

The preparation of representative non-limiting examples of providedcompounds are described below.

Example 1:2-(4-(5-(1-(2-Cyanophenyl)-3,3-dimethylpiperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-52

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: tert-Butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate

Tert-Butyl 3,3-dimethyl-4-oxo-piperidine-1-carboxylate (2.5 g, 11 mmol)was dissolved in MeOH (50 mL) and ammonium formate (3.95 g, 62.69 mmol)and NaBH₃CN (740 mg, 11.77 mmol) were added. The reaction mixture wasstirred for 17 h at rt and then purified by reversed-phase column togive tert-butyl 4-amino-3,3-dimethyl-piperidine-1-carboxylate (0.4 g,1.65 mmol, 15%) as a white solid. ESI-MS (EI⁺, m/z): 173.3 [M−56]⁺.

Step 2: 3,3-Dimethylpiperidin-4-amine hydrochloride salt

Tert-Butyl 4-amino-3,3-dimethyl-piperidine-1-carboxylate (2 g, 5.5 mmol)was dissolved in 4 M HCl/dioxane (25 mL). The mixture was stirred at rtfor 3 h. The reaction mixture was concentrated to give3,3-dimethylpiperidin-4-amine (1 g, 4.97 mmol, 90%, 2 HCl) as a yellowsolid. ESI-MS (EI⁺, m/z): 129.1 [M+H]⁺.

Step 3: 2-(4-Amino-3,3-dimethylpiperidin-1-yl) benzonitrile

3,3-Dimethylpiperidin-4-amine (350 mg, 1.74 mmol, 2HCl) was dissolved inDMF (10 mL) then K₂CO₃ (1.44 g, 10.44 mmol) and 2-fluorobenzonitrile(210.74 mg, 1.74 mmol) were added. The mixture was stirred at 120° C.for 17 h. The mixture was cooled down to rt. Then water (150 mL) wasadded and extracted with EtOAc (3×50 mL). The combined organic layerswere concentrated and the residue was purified by column chromatography(DCM/MeOH=30). 2-(4-amino-3,3-dimethyl-1-piperidyl) benzonitrile (30 mg,0.11 mmol, 8%) was obtained as a yellow oil. ESI-MS (EI⁺, m/z): 230.2[M+H]⁺.

Step 4: Methyl5-(1-(2-cyanophenyl)-3,3-dimethylpiperidin-4-ylamino)-2,4-dimethylbenzoate

2-(4-amino-3,3-dimethyl-1-piperidyl)benzonitrile (100 mg, 0.44 mmol),methyl 5-bromo-2,4-dimethyl-benzoate (116.61 mg, 0.48 mmol), tBuONa(83.8 mg, 0.87 mmol), BrettPhos (46.81 mg, 0.087 mmol), and Pd₂(dba)₃(199.72 mg, 0.2 mmol) were dissolved in toluene (5 mL) and the mixturewas stirred at 85° C. for 17 h. The mixture was purified by columnchromatography (PE/EA=10/1) to afford methyl5-[[1-(2-cyanophenyl)-3,3-dimethyl-4-piperidyl]amino]-2,4-dimethyl-benzoate(30 mg, 0.076 mmol, 17%) as a yellow oil. ESI-MS (EI⁺, m/z): 392.0[M+H]⁺.

Step 5:5-(1-(2-Cyanophenyl)-3,3-dimethylpiperidin-4-ylamino)-2,4-dimethylbenzoicAcid

To a solution of methyl5-[[1-(2-cyanophenyl)-3,3-dimethyl-4-piperidyl]amino]-2,4-dimethyl-benzoate(30 mg, 0.076 mmol) in H₂O (3 mL) and MeOH (5 mL) was added LiOH.H₂O(32.15 mg, 0.76 mmol). The mixture was stirred at 60° C. for 17 h. Themixture was concentrated and acidified with 1 N HCl and extracted withEtOAc. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated to give crude5-[[1-(2-cyanophenyl)-3,3-dimethyl-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (30 mg, 0.07 mmol, 90%) as a yellow oil. ESI-MS (EI⁺, m/z): 378.3[M+H]⁺.

Step 6:2-(4-(5-(1-(2-Cyanophenyl)-3,3-dimethylpiperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl) benzenesulfonamide

Following the amide coupling HATU method2-(4-(5-(1-(2-Cyanophenyl)-3,3-dimethylpiperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamideI-52 was obtained as a white solid. ESI-MS (EI⁺, m/z): 601.3 [M+H]⁺. ¹HNMR (500 MHz, MeOD-d₄) δ 8.04-7.93 (m, 1H), 7.70-7.52 (m, 4H), 7.37 (t,J=7.6 Hz, 1H), 7.21 (dd, J=8.2, 4.0 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H),6.97 (s, 1H), 6.61 (s, 1H), 4.01 (m, 1H), 3.53 (m, 3H), 3.38 (m, 1H),3.29 (m, 1H), 3.22-3.09 (m, 2H), 3.00 (m, 3H), 2.82 (m, 1H), 2.20 (d,J=7.5 Hz, 6H), 2.00 (m, 1H), 1.90 (m, 1H), 1.32 (m, 1H), 1.26 (s, 3H),1.06 (s, 3H).

Example 2: (R)-2-(4-(2,4-Dimethyl-5-(3-methyl-4-(pyridin-2-yl)piperazine-1-carbonyl) phenylamino) piperidin-1-yl) benzonitrile, I-45

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method A and the separation method wasfollowing Method D.

Step 1: (R)-2-Methyl-1-(pyridin-2-yl)piperazine hydrochloride salt

Tert-Butyl (3R)-3-methyl-4-(2-pyridyl)piperazine-1-carboxylate (300 mg,0.54 mmol) was dissolved in HCl/dioxane (4 M, 10 mL). The mixture wasstirred at rt for 3 h and concentrated to give crude(2R)-2-methyl-1-(2-pyridyl)piperazine (200 mg, 0.33 mmol, 60%, HCl) as ayellow oil. ESI-MS (EI⁺, m/z): 178.3 [M+H]⁺.

Step 2:(R)-2-(4-(2,4-Dimethyl-5-(3-methyl-4-(pyridin-2-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile

Followed the amide coupling EDCI/HOBT method to obtain(R)-2-(4-(2,4-Dimethyl-5-(3-methyl-4-(pyridin-2-yl)piperazine-1-carbonyl) phenylamino)piperidin-1-yl)benzonitrile I-45 as awhite solid. ESI-MS (EI⁺, m/z): 509.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.19 (d, J=4.7 Hz, 1H), 7.51 (m, 3H), 6.98 (m, 3H), 6.75-6.33 (m, 3H),4.47 (m, 2H), 4.02 (m, 1H), 3.66-2.92 (m, 10H), 2.20 (m, 8H), 1.73 (s,2H), 1.30-0.99 (m, 3H).

Example 3: (R)-tert-Butyl 4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate, I-7

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method A and the separation method wasfollowing Method D.

Step 1: (R)-tert-Butyl-2-(hydroxyethyl)piperazine-1-carboxylate

(R)-4-Benzyl 1-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate(2 g, 4.85 mmol) was dissolved in MeOH (50 mL), Pd/C (480 mg, 3.95 mmol)was added and stirred at rt for 4 h under H₂. The reaction mixture wasfiltered and the filtrate was concentrated to give crude(R)-tert-butyl-2-(hydroxymethyl)piperazine-1-carboxylate (900 mg, 4.16mmol, 85%) as a colorless oil. ESI-MS (EI⁺, m/z): 217.3 [M+H]⁺.

Step 2:(R)-tert-Butyl-4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate

Followed the amide coupling HATU method to obtain(R)-tert-Butyl-4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate I-7 as a red oil. ESI-MS (EI⁺, m/z): 548.3[M+H]⁺. ¹H NMR (500 MHz, MeOD-d₄) δ 7.71-7.51 (m, 2H), 7.21 (d, J=8.5Hz, 1H), 7.08 (t, J=7.6 Hz, 1H), 6.97 (m, 1H), 6.50 (m, 1H), 3.79 (m,9H), 3.26-2.91 (m, 5H), 2.29-2.04 (m, 8H), 1.79 (m, 2H), 1.49 (s, 9H).

Example 4: (R)-2-(4-(5-(3-(Hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile, I-6

Synthetic Scheme:

The analysis method was following Method B.

Step 1:(R)-2-(4-(5-(3-(Hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

tert-Butyl-(2R)-4-[5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoyl]-2-(hydroxymethyl)piperazine-1-carboxylate(500 mg, 0.91 mmol) in 4 M HCl/dioxane (10 mL) was stirred at rt for 3h. The solvent was concentrated and the residue was taken up in DCM. Themixture was washed with sat. NaHCO₃, the organic layer was dried overNa₂SO₄, filtered and concentrated to give2-[4-[5-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethyl-anilino]-1-piperidyl]benzonitrile1-6 (300 mg, 0.67 mmol, 73%) as a yellow solid. ESI-MS (EI⁺, m/z): 448.3[M+H]⁺. ¹H NMR (500 MHz, MeOD-d₄) δ 7.68-7.51 (m, 2H), 7.21 (d, J=8.3Hz, 1H), 7.08 (t, J=7.6 Hz, 1H), 6.95 (m, 1H), 6.62-6.43 (m, 1H), 4.60(m, 1H), 3.69-3.35 (m, 6H), 3.20-2.60 (m, 7H), 2.16 (m, 8H), 1.78 (m,2H).

Example 5: 2-(4-(5-(1-(3-Methoxyphenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl) piperazin-1-yl)benzenesulfonamide, I-5

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method A and the separation method wasfollowing Method D.

Step 1: tert-Butyl 1-(3-methoxyphenyl)piperidin-4-ylcarbamate

tert-Butyl N-(4-piperidyl) carbamate (1 g, 5 mmol),1-bromo-3-methoxy-benzene (933.3 mg, 5 mmol), Cs₂CO₃ (3.25 g, 10 mmol)and Pd₂(dba)₃ (914.72 mg, 1 mmol) were dissolved in toluene (30 mL) andthe mixture was stirred at 100° C. for 17 h. The mixture was extractedand purified via preparative HPLC to give tert-butylN-[1-(3-methoxyphenyl)-4-piperidyl] carbamate (600 mg, 1.57 mmol, 31%)as a yellow solid. ESI-MS (EI⁺, m/z): 307.2 [M+H]⁺.

Step 2: 1-(3-Methoxyphenyl)piperidin-4-amine

tert-Butyl N-[1-(3-methoxyphenyl)-4-piperidyl] carbamate (200 mg, 0.65mmol) in 4 M HCl/dioxane (0.65 mmol, 10 mL) was stirred at rt for 3 h.The solvent was concentrated and the residue was taken up in DCM. Themixture was washed with sat. NaHCO₃, the organic layer was dried overNa₂SO₄, filtered and concentrated to give 1-(3-methoxyphenyl)piperidin-4-amine (100 mg, 0.48 mmol, 74%) as a yellow oil. ESI-MS (EI⁺,m/z): 207.2 [M+H]⁺.

Step 3: Methyl5-(1-(3-methoxyphenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate

A mixture of 1-(3-methoxyphenyl) piperidin-4-amine (100 mg, 0.48 mmol),methyl 5-bromo-2,4-dimethyl-benzoate (117.85 mg, 0.48 mmol), BINAP(60.37 mg, 0.97 mmol), Cs₂CO₃ (315.9 mg, 0.97 mmol) and Pd₂(dba)₃ (88.8mg, 0.097 mmol) in dioxane (5 mL) was stirred at 100° C. for 17 h. Themixture was purified by column chromatography (PE/EA=5/1) to give methyl5-[[1-(3-methoxyphenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate (50 mg,0.14 mmol, 28%) as a yellow oil. ESI-MS (EI⁺, m/z): 369.3 [M+H]⁺.

Step 4: 5-(1-(3-Methoxyphenyl)piperidin-4-ylamino)-2,4-dimethylbenzoicAcid

Methyl 5-[[1-(3-methoxyphenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate(50 mg, 0.14 mmol) dissolved in THF (5 mL) and H₂O (3 mL) and LiOH.H₂O(20 mg, 0.48 mmol) was added. The mixture was stirred at 60° C. for 17h. The mixture was concentrated and acidified with 1 M HCl and extractedwith EtOAc. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated to give crude5-[[1-(3-methoxyphenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoic acid (40mg, 0.1 mmol, 83%) as a yellow oil. ESI-MS (EI⁺, m/z): 355.2 [M+H]⁺.

Step 5:2-(4-(5-(1-(3-Methoxyphenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

Followed the amide coupling general EDCI/HOBT method to obtain2-(4-(5-(1-(3-Methoxyphenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamideI-5 as a white solid. ESI-MS (EI⁺, m/z): 578.2 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.87 (dd, J=7.9, 1.5 Hz, 1H), 7.66-7.51 (m, 2H), 7.43-7.29(m, 1H), 7.09 (t, J=8.2 Hz, 1H), 6.97 (s, 2H), 6.86 (s, 1H), 6.54 (dd,J=8.3, 2.0 Hz, 1H), 6.45 (dd, J=6.6, 4.4 Hz, 2H), 6.33 (dd, J=8.1, 2.1Hz, 1H), 4.44 (d, J=8.2 Hz, 1H), 4.04-3.60 (m, 7H), 3.42 (m, 3H),3.08-2.69 (m, 6H), 2.13-2.01 (m, 6H), 1.96 (m, 2H), 1.55 (m, 2H).

Example 6: (S)-2-(4-(5-(3-(Hydroxymethyl)-4-(1-methyl-1H-tetrazol-5-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino) piperidin-1-yl)benzonitrile, I-91

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: (S)-Benzyl3-((tert-butyldimethylsilyloxy)methyl)-4-cyanopiperazine-1-carboxylate

Benzyl(3S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazine-1-carboxylate(120 mg, 0.33 mmol) was dissolved in DCM (15 mL) and NaHCO₃(110.62 mg,1.32 mmol, 151.53 uL) was added at 0° C., carbononitridic bromide (69.73mg, 0.66 mmol) was added and stirred at 0° C. for 1 h. The mixture wasstirred at rt for 16 h. LCMS showed desired product. The mixture wasextracted with DCM, and the organic layer was washed with aq. NaHCO₃,brine and dried over Na₂SO₄, filtered and the filtrate was concentratedto give crude benzyl(3S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-cyano-piperazine-1-carboxylate(100 mg, 0.2 mmol, 62%) as a yellow oil. ESI-MS (EI⁺, m/z): 390.3[M+H]⁺.

Step 2: (S)-Benzyl3-(hydroxymethyl)-4-(1H-tetrazol-5-yl)piperazine-1-carboxylate

Benzyl (3S)-3-[[tert-butyl (dimethyl) silyl]oxymethyl]-4-cyano-piperazine-1-carboxylate (100 mg, 0.2 mmol), NaN₃(66.75 mg, 1.03 mmol), and NH₄Cl (68.65 mg, 1.28 mmol) were dissolved inDMF (10 mL) and the mixture was stirred at 100° C. for 17 h. The mixturewas extracted with EtOAc and the organic layer was washed with brine andpurified via preparative HPLC (acid) to give benzyl(3S)-3-(hydroxymethyl)-4-(1H-tetrazol-5-yl)piperazine-1-carboxylate (50mg, 0.16 mmol, 61%) as a white solid. ESI-MS (EI⁺, m/z): 319.2 [M+H]⁺.

Step 3: (S)-Benzyl3-(hydroxymethyl)-4-(1-methyl-1H-tetrazol-5-yl)piperazine-1-carboxylate

Benzyl (3S)-3-(hydroxymethyl)-4-(1H-tetrazol-5-yl)piperazine-1-carboxylate (50 mg, 0.16 mmol), MeI (66.88 mg, 0.47 mmol)and K₂CO₃ (65.13 mg, 0.47 mmol) were dissolved in DMF (5 mL) and themixture was stirred at rt for 17 h. Silica gel purification gave benzyl(3S)-3-(hydroxymethyl)-4-(1-methyltetrazol-5-yl)piperazine-1-carboxylate(30 mg, 0.09 mmol, 57%) as a yellow oil. ESI-MS (EI⁺, m/z): 333.7[M+H]⁺.

Step 4: (S)-(1-(1-Methyl-1H-tetrazol-5-yl)piperazin-2-yl)methanol

Benzyl(3S)-3-(hydroxymethyl)-4-(1-methyltetrazol-5-yl)piperazine-1-carboxylate(30 mg, 0.09 mmol) and Pd/C (20 mg) were dissolved in MeOH (10 mL). Themixture was stirred at rt for 17 h under H₂. The reaction mixture wasfiltered and the filtrate was concentrated to give[(2S)-1-(1-methyltetrazol-5-yl)piperazin-2-yl]methanol (10 mg, 0.05mmol, 55%) as a white solid. ESI-MS (EI⁺, m/z): 199.2 [M+H]⁺.

Step 5:(S)-2-(4-(5-(3-(Hydroxymethyl)-4-(1-methyl-1H-tetrazol-5-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

Followed the amide coupling general EDCI/HOBT method to obtain(S)-2-(4-(5-(3-(Hydroxymethyl)-4-(1-methyl-1H-tetrazol-5-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrileI-91 as a white solid. ESI-MS (EI⁺, m/z): 530.3 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.72-7.39 (m, 2H), 7.10-6.88 (m, 3H), 6.48 (m, 1H), 4.82 (m,1H), 4.36 (m, 1H), 4.17 (s, 3H), 3.85-3.07 (m, 12H), 2.98 (m, 2H), 2.17(m, 8H), 1.68 (m, 2H).

Example 7:(R)-2-(4-(2,4-Dimethyl-5-(4-(3-(S-methylsulfonimidoyl)pyridin-2-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile,I-94

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 2-Chloro-3-(methylthio)pyridine

A solution of 2-chloropyridin-3-amine (24.4 g, 189.79 mmol) intetrafluoroboric acid (80 mL) and ethanol (95 percent, 75 mL) was cooledto 5° C. A solution of sodium nitrite (13.75 g, 199.28 mmol) in water(40 mL) was added in one portion. Diethyl ether (200 mL) was added andthe resulting precipitate removed by filtration then dissolved inacetonitrile (400 mL) and cooled down to 0° C. Sodium thiomethoxide(26.6 g, 75.92 mmol, 20% purity) was added portionwise and the reactionstirred at rt for 2 h. The reaction mixture was filtered and thefiltrate concentrated then passed through a plug of silica, eluting with10 percent ethyl acetate/PE, to give 2-chloro-3-methylsulfanyl-pyridine(6 g, 19% yield) as a pale white solid. MS (EI⁺, m/z): 160.2 [M+H]⁺.

Step 2: 2-Chloro-3-(methylsulfinyl)pyridine

To a suspension of 2-chloro-3-methylsulfanyl-pyridine (13.2 g, 82.69mmol) in THF (100 mL) at 0° C. was added dropwise a solution of m-CPBA(15.7 g, 90.96 mmol) in THF (40 mL) at a rate such that the temperatureof the reaction mixture did not exceed 10° C. over the course of theaddition. The reaction mixture was then allowed to warm to rt followedby stirring at rt overnight. The solvent was removed, the residue wasextracted with DCM (250 mL×2) and 2 N NaOH (100 mL), washed with 2 NNaOH (800 mL×2), brine (80 mL), and concentrated to give a residue whichwas purified by flash column (from 0% to 20% and then to 50% of EtOAc inPE) to afford 2-chloro-3-methylsulfinyl-pyridine (20.8 g, 82%) as a palewhite solid. ESI-MS (EI⁺, m/z): 175.2 [M+H]⁺.

Step 3: 2-Chloro-3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridine

To a suspension of tert-butyl carbamate (6.67 g, 56.94 mmol),2-chloro-3-methylsulfinyl-pyridine (5 g, 28.47 mmol), MgO (4.70 g,113.88 mmol) and Rh₂(OAc)₄ (503.35 mg, 1.14 mmol) in DCM (20 mL) wasadded portionwise PhI(OAc)₂ (18.33 g, 56.94 mmol) and the reactionmixture stirred at 25° C. for 17 h. The reaction mixture was filtered,washed with DCM (50 mL×2), and concentrated to give a residue which waspurified via preparative HPLC (TFA, eluting from 10% to 20% of MeCN inwater) to afford2-chloro-3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridine (4.2 g,25%) as a pale white solid. ESI-MS (EI⁺, m/z): 234.9 [M-55]⁺.

Step 4:1-(3-(N-tert-Butoxycarbonyl-S-methylsulfonimidoyl)pyridin-2-yl)piperazine

A mixture of2-chloro-3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridine (300mg, 1.03 mmol) and piperazine (354.90 mg, 4.12 mmol) in DMF (3 mL) wasstirred at 110° C. for 1.5 h. The reaction mixture was filtered and thefiltrate was purified via preparative HPLC (TFA, 5% to 10% of MeCN inwater) to afford1-(3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridin-2-yl)piperazine(300 mg, 85% yield) as a brown solid. ESI-MS (EI⁺, m/z): 341.0 [M+H]⁺.Chiral separation gave(R)-2-piperazine-3-(N-tert-butoxycarbonyl-methylsulfonimidoyl) pyridine(170 mg, 34%) as a colorless oil and(S)-2-piperazine-3-(N-tert-butoxycarbonyl-methylsulfonimidoyl) pyridine(180 mg, 36%) as a colorless oil.

Step 5:(R)-2-(4-(2,4-Dimethyl-5-(4-(3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridin-2-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile

To a solution of(R)-2-piperazine-3-(N-tert-butoxycarbonyl-methylsulfonimidoyl)pyridine(160 mg, 469.98 umol) and5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoic acid(197.07 mg, 563.98 umol) in DMF (1.50 mL) was added EDCI (180.19 mg,939.96 umol) and HOBT (95.26 mg, 704.97 umol). The mixture was stirredat rt for 17 h. The reaction mixture was extracted with EtOAc (10 mL×3)and water (5 mL), dried and concentrated to afford(R)-2-(4-(2,4-dimethyl-5-(4-(3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridin-2-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile(300 mg, 85% yield) as a brown oil which used directly in the next step.ESI-MS (EI+, m/z): 671.9 [M+H]+.

Step 6:(R)-2-(4-(2,4-Dimethyl-5-(4-(3-(S-methylsulfonimidoyl)pyridin-2-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile

A mixture of(R)-2-(4-(2,4-dimethyl-5-(4-(3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridin-2-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile(160 mg, 238.15 umol) in TFA (1 mL) and DCM (1 mL) was stirred at 0° C.for 2 h. The solvent was removed in vacuo at rt to give a residue, DIPEAwas added to adjust the pH to 8, the crude material was then filteredand purified via preparative HPLC (NH₄HCO₃) to afford2-[4-[2,4-dimethyl-5-[4-[3-(methylsulfonimidoyl)-2-pyridyl]piperazine-1-carbonyl]anilino]-1-piperidyl]benzonitrileI-94 (43.80 mg, 32% yield) as a white solid. The stereochemistry wasarbitrarily assigned. ESI-MS (EI⁺, m/z): 572.3 [M+H]; ¹H NMR (400 MHz,MeOD-d₄) δ 8.59 (dd, J=4.8, 1.8 Hz, 1H), 8.43 (dd, J=7.9, 1.8 Hz, 1H),7.68-7.51 (m, 2H), 7.41 (dd, J=7.9, 4.8 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H),7.08 (t, J=7.4 Hz, 1H), 6.98 (s, 1H), 6.57 (s, 1H), 4.00 (s, 2H), 3.55(d, J=22.4 Hz, 5H), 3.43 (s, 3H), 3.22 (s, 5H), 3.05 (t, J=10.6 Hz, 3H),2.19 (d, J=10.5 Hz, 8H), 1.77 (s, 2H).

Example 8:(S)-2-(4-(2,4-Dimethyl-5-(4-(3-(S-methylsulfonimidoyl)pyridin-2-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile,I-93

Synthetic Scheme:

Procedures and Characterization:

The procedure for (S)-1-(3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridin-2-yl) piperazine was same as for example 7.

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 5:(S)-2-(4-(2,4-Dimethyl-5-(4-(3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridin-2-yl) piperazine-1-carbonyl) phenylamino) piperidin-1-yl)benzonitrile

To a solution of(S)-1-(3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridin-2-yl)piperazine(170 mg, 499.35 umol) and5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoic acid(209.39 mg, 599.22 umol) in DMF (1.50 mL) was added EDCI (191.45 mg,998.70 umol) and HOBT (101.21 mg, 749.03 umol). The mixture was stirredat rt for 17 h. Then the reaction mixture was extracted with EtOAc (10mL×3) and water (5 mL), dried and concentrated to afford(S)-2-(4-(2,4-dimethyl-5-(4-(3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridin-2-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile(300 mg, 80% yield, 90% purity) as a brown oil. MS (EI⁺, m/z): 671.9[M+H]⁺.

Step 6: (S)-2-(4-(2,4-Dimethyl-5-(4-(3-(S-methylsulfonimidoyl)pyridin-2-yl) piperazine-1-carbonyl) phenylamino) piperidin-1-yl)benzonitrile

A mixture of(S)-2-(4-(2,4-dimethyl-5-(4-(3-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)pyridin-2-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile(170 mg, 253.03 umol) in TFA (1 mL) and DCM (1 mL) was stirred at 0° C.for 2 h. The solvent was removed in vacuum at rt to give a residue,DIPEA was added to adjust the pH to 8. The residue was filtered andpurified via preparative HPLC (NH₄HCO₃) to afford2-[4-[2,4-dimethyl-5-[4-[3-(methylsulfonimidoyl)-2-pyridyl]piperazine-1-carbonyl]anilino]-1-piperidyl]benzonitrileI-93, (35.10 mg, 24% yield) as a white solid. The stereochemistry wasarbitrarily assigned. ESI-MS (EI⁺, m/z): 572.3 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD-d₄) δ 8.59 (dd, J=4.8, 1.8 Hz, 1H), 8.43 (dd, J=7.9, 1.8 Hz, 1H),7.70-7.47 (m, 2H), 7.41 (dd, J=7.9, 4.8 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H),7.08 (t, J=7.5 Hz, 1H), 6.98 (s, 1H), 6.57 (s, 1H), 4.00 (s, 2H), 3.55(d, J=21.4 Hz, 5H), 3.43 (s, 3H), 3.21 (d, J=5.1 Hz, 3H), 3.04 (t,J=10.9 Hz, 2H), 2.19 (d, J=10.5 Hz, 8H), 1.78 (s, 2H).

Example 9:2-(4-(5-(1-(2-Cyano-6-fluorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)-6-fluorobenzenesulfonamide,I-92

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: tert-Butyl 1-(2-cyano-6-fluorophenyl)piperidin-4-ylcarbamate

A mixture of 2-bromo-3-fluoro-benzonitrile (3 g, 15 mmol), tert-butylN-(4-piperidyl)carbamate (3.61 g, 18 mmol), Pd₂(dba)₃ (1.37 g, 1.50mmol), BINAP (932.95 mg, 1.50 mmol) and tBuONa (2.16 g, 22.50 mmol) intoluene (50 mL) was charged with N₂ for three times, then stirred at 90°C. for 17 h. The reaction mixture was cooled down to rt and concentratedto give a residue which was purified by a flash column (10% to 22% ofEtOAc in PE) to afford tert-butylN-[1-(2-cyano-6-fluoro-phenyl)-4-piperidyl] carbamate (4 g, 83% yield)as a yellow solid. MS (EI⁺, m/z): 320.1 [M+H]⁺.

Step 2: 2-(4-Aminopiperidin-1-yl)-3-fluorobenzonitrile

A mixture of tert-butyl N-[1-(2-cyano-6-fluoro-phenyl)-4-piperidyl]carbamate (3 g, 9.39 mmol) in HCl/dioxane (4 M, 15 mL) was stirred at rtfor 2 h. The reaction mixture was filtered, washed with Et₂O (5 mL) anddried to afford 2-(4-amino-1-piperidyl)-3-fluoro-benzonitrile (2 g, 83%yield, HCl salt) as a pale white solid. ESI-MS (EI⁺, m/z): 220.2 [M+H]⁺.

Step 3: Methyl5-(1-(2-cyano-6-fluorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate

A mixture of 2-(4-amino-1-piperidyl)-3-fluoro-benzonitrile (1.50 g, 6.84mmol), methyl 5-bromo-2,4-dimethyl-benzoate (1.39 g, 5.70 mmol),tris(dibenzylideneacetone)dipalladium(O) (522.05 mg, 570 umol),dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane(612.02 mg, 1.14 mmol), cesium carbonate (5.57 g, 17.10 mmol) anddioxane (20 mL) was stirred at 110° C. for 17 h. The reaction mixturewas cooled down to rt, filtered, and concentrated to give a residuewhich was purified by a flash column (5% to 10% of EtOAc in PE) toafford methyl5-[[1-(2-cyano-6-fluoro-phenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate(1.80 g, 83% yield) as a red solid. ESI-MS (EI⁺, m/z): 382.2 [M+H]⁺.

Step 4:5-(1-(2-Cyano-6-fluorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoicAcid

To a solid of methyl5-[[1-(2-cyano-6-fluoro-phenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate(500 mg, 1.31 mmol) was added BBr₃ (1 M, 5 mL) at rt, then stirred at rtfor 2 h. The reaction mixture was poured into 50 mL of DCM, washed withsat. NaHCO₃(15 mL), the aqueous layer was extracted with DCM/MeOH(v/v=10:1, 25 mL×2), dried, and concentrated to give a residue which waspurified by a flash column (20% to 30% of EA in PE) to afford5-[[1-(2-cyano-6-fluoro-phenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (300 mg, 62% yield) as a pale white solid. MS (EI⁺, m/z): 368.2[M+H]⁺.

Step 5: 2-(4-(5-(1-(2-Cyano-6-fluorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)-6-fluorobenzenesulfonamide

Followed the amide coupling general EDCI/HOBT method to obtain2-(4-(5-(1-(2-Cyano-6-fluorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)-6-fluorobenzenesulfonamide1-92 as a white solid. ESI-MS (EI⁺, m/z): 609.3 [M+H]⁺; ¹H NMR (500 MHz,CD3OD) δ 7.58 (td, J=8.2, 6.0 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.38 (dd,J=12.2, 8.2 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.16 (td, J=8.0, 4.6 Hz,1H), 7.15-7.02 (m, 1H), 6.97 (s, 1H), 6.58 (s, 1H), 3.68-3.41 (m, 5H),3.43-3.35 (m, 2H), 3.06 (dd, J=99.3, 41.0 Hz, 4H), 2.28-2.10 (m, 7H),1.88-1.62 (m, 2H).

Example 10:2-[4-[2,4-Dimethyl-5-[(3S)-3-methyl-4-(2-pyridyl)piperazine-1-carbonyl]anilino]-1-piperidyl]benzonitrile,I-34

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: (S)-tert-Butyl-3-methyl-4-(pyridin-2-yl)piperazine-1-carboxylate

A mixture of (S)-tert-butyl-3-methylpiperazine-1-carboxylate (2.0 g,10.0 mmol), 2-bromopyridine (1.9 g, 12.0 mmol), potassium tert-butylate(1.57 g, 14.0 mmol), 2,2′-(bisphenylphosphino)-1,1′-binaphthalene (311mg, 0.5 mmol) and tris(dibenzylideneacetone)dipalladium (915 mg, 1.0mmol) in dioxane (10 mL) was stirred at 110° C. for 16 h under N₂. Thenthe reaction mixture was filtered, concentrated, poured into water (100mL) and extracted with EtOAc (100 mL×2). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated. Further purificationwas on column chromatography eluting with PE/EA from 100/1 to 10/1 toobtain (S)-tert-butyl-3-methyl-4-(pyridin-2-yl) piperazine-1-carboxylate(1.25 g, 23%) as light-yellow oil. ESI-MS (EI⁺, m/z): 278.3 [M+H]⁺.

Step 2: (S)-2-Methyl-1-(pyridin-2-yl)piperazine

A mixture of(S)-tert-butyl-3-methyl-4-(pyridin-2-yl)piperazine-1-carboxylate (299mg, 1.08 mmol) and HCl in dioxane (4 M) (10.8 mmol, 2.7 mL) was stirredat rt for 16 h. The mixture was concentrated, washed with EtOAc (50mL×3), the pH adjusted to 6-7, then extracted with EtOAc (50 mL×3),dried and concentrated to obtain(S)-2-methyl-1-(pyridin-2-yl) piperazine(120 mg, 61.4%) as a light-yellow oil. ESI-MS (EI⁺, m/z): 178.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.08 (dd, J=4.8, 1.5 Hz, 1H), 7.48 (m, 1H),6.71 (t, J=11.2 Hz, 1H), 6.59-6.51 (m, 1H), 4.40-4.26 (m, 1H), 3.92-3.81(m, 1H), 2.98-2.90 (m, 1H), 2.80 (m, 3H), 2.65-2.56 (m, 1H), 1.08 (d,J=6.6 Hz, 3H).

Step 3:2-[4-[2,4-Dimethyl-5-[(3S)-3-methyl-4-(2-pyridyl)piperazine-1-carbonyl]anilino]-1-piperidyl]benzonitrile

Followed the amide coupling general EDCI/HOBT method to obtain2-[4-[2,4-dimethyl-5-[(3S)-3-methyl-4-(2-pyridyl)piperazine-1-carbonyl]anilino]-1-piperidyl]benzonitrile1-34 as a white solid. ESI-MS (EI⁺, m/z): 509.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.11 (d, J=3.2 Hz, 1H), 7.68 (d, J=7.0 Hz, 1H), 7.55 (dt,J=14.4, 7.2 Hz, 2H), 7.16 (d, J=8.2 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H),6.89 (s, 1H), 6.76 (d, J=8.6 Hz, 1H), 6.66-6.59 (m, 1H), 6.42 (s, 1H),4.55 (dd, J=51.4, 43.8 Hz, 2H), 4.03 (dd, J=55.5, 13.1 Hz, 1H),3.54-3.39 (m, 3H), 2.98 (t, J=29.4 Hz, 6H), 2.12-1.63 (m, 11H),1.08-0.86 (m, 3H).

Example 11:2-(4-(5-(3,3-Dimethyl-4-phenylpiperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-119

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: tert-Butyl-3-oxopiperazine-1-carboxylate

To a solution of piperazin-2-one (22 g, 219.7 mmol) in THF (300 mL) wasadded a mixture of NaHCO₃ (29.53 g, 307.6 mmol) in H₂O (100 mL), (Boc)₂O(43.16 g, 197.8 mmol), then the reaction solution was stirred at rt for16 h. The mixture was concentrated, poured into water (100 mL) andextracted with EtOAc (100 mL×2). The combined organic layers were driedover Na₂SO₄, filtered and concentrated to obtaintert-butyl-3-oxopiperazine-1-carboxylate (40 g, 91%) as white solid.ESI-MS (EI⁺, m/z): 145.2[M+H−56]. ¹H NMR (500 MHz, CDCl₃) δ 4.08 (s,2H), 3.62 (t, J=5.2 Hz, 2H), 3.37 (s, 2H), 1.47 (s, 9H).

Step 2:tert-Butyl-4-[(4-methoxyphenyl)methyl]-3-oxo-piperazine-1-carboxylate

To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (20.02 g, 100mmol) in DMF (50 mL) was added NaH (3.96 g, 165 mmol) at rt and thereaction mixture stirred for 30 min. Then1-(chloromethyl)-4-methoxy-benzene (17.23 g, 110 mmol) was dropped inthe mixture and stirred at rt for another 2 h. The reaction mixture wasquenched with HCl (0.2 M, 30 mL), extracted with DCM (100 mL×3), driedand concentrated. Further purification was carried out by columnchromatography eluting with PE/EtOAc=10/1 to obtaintert-butyl-4-[(4-methoxyphenyl)methyl]-3-oxo-piperazine-1-carboxylate(17.20 g, 54%) as white solid. ESI-MS (EI⁺, m/z): 265.2 [M+H-56]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.20 (d, J=8.6 Hz, 2H), 6.90-6.82 (m, 2H), 4.55(s, 2H), 4.12 (d, J=17.7 Hz, 2H), 3.80 (s, 3H), 3.61-3.52 (m, 2H),3.29-3.19 (m, 2H), 1.47 (s, 9H).

Step 3:(S)-(4-((4-(3-chloropyridin-2-yl)piperazin-1-yl)methyl)-1,5-dimethyl-1H-pyrrol-2-yl)(4-(4-fluorophenyl)-2-methylpiperazin-1-yl)methanone

tert-Butyl-4-[(4-methoxyphenyl)methyl]-3-oxo-piperazine-1-carboxylate(10 g, 31.21 mmol) was dissolved in HCl in dioxane (4 M) (16 mL, 62.42mmol) and the mixture was stirred at rt for 2 h. Then the mixture wasquenched with water (100 mL) and adjusted the pH to 6-7, extracted withEtOAc (100 mL×3), dried and concentrated to obtain1-[(4-methoxyphenyl)methyl]piperazin-2-one (5.80 g, 84%) as white solid.ESI-MS (EI⁺, m/z): 221.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.20 (d,J=8.4 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 4.54 (s, 2H), 3.80 (d, J=3.6 Hz,3H), 3.58 (s, 2H), 3.21 (t, J=5.2 Hz, 2H), 3.09-2.98 (m, 2H).

Step 4: 1-[(4-Methoxyphenyl) methyl]-4-phenyl-piperazin-2-one

To a mixture of 1-[(4-methoxyphenyl) methyl] piperazin-2-one (3 g, 13.62mmol), iodobenzene (2.78 g, 13.62 mmol), XPhos (324 mg, 680 umol),tBuONa (1.83 g, 19.07 mmol) in dioxane (3 mL) was added Pd₂(dba)₃ (623mg, 680 umol), then stirred at 100° C. for 16 h. The mixture wasfiltered, concentrated and washed with water (100 mL), extracted withEtOAc (100 mL×3), dried and concentrated. Further purification wascarried out by column chromatography eluting with PE/EA from 20/1 to 5/1to obtain 1-[(4-methoxyphenyl)methyl]-4-phenyl-piperazin-2-one (2.32 g,57%) as yellow solid. ESI-MS (EI⁺, m/z): 297.3 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.33-7.19 (m, 4H), 6.89 (m, 5H), 4.61 (s, 2H), 3.95 (s, 2H),3.80 (s, 3H), 3.39 (m, 4H).

Step 5: 1-[(4-Methoxyphenyl)methyl]-3-methyl-4-phenyl-piperazin-2-one

To a mixture of diisopropylamine (2.52 g, 24.95 mmol) in THF (20 mL) wasadded n-BuLi (50 mmol, 10 mL) at −78° C. The reaction mixture wasstirred at rt for 20 min. DMPU (1.28 g, 49.90 mmol) was added andstirred at −78° C. for another 1 h. A solution of1-[(4-methoxyphenyl)methyl]-4-phenyl-piperazin-2-one (1.48 g, 4.99 mmol)in THF (20 mL) was added and stirred at −78° C. for 2 h. Theniodomethane (3.54 g, 24.95 mmol) was added and stirred at −78° C.overnight. The reaction mixture was quenched with NH₄Cl (aq.), extractedwith DCM (100 mL×3), dried and concentrated. Further purification wascarried by a flash column eluting with PE/EA from 6/1 to 3/1 to afford1-[(4-methoxyphenyl)methyl]-3-methyl-4-phenyl-piperazin-2-one (623 mg,40%) as a yellow gum. ESI-MS (EI⁺, m/z): 311.0 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.30-7.16 (m, 4H), 6.91-6.76 (m, 5H), 5.26 (s, 1H), 4.68 (d,J=14.5 Hz, 1H), 4.53-4.37 (m, 2H), 3.78 (s, 3H), 3.50-3.17 (m, 4H), 1.41(d, J=6.9 Hz, 3H).

Step 6:1-[(4-Methoxyphenyl)methyl]-3,3-dimethyl-4-phenyl-piperazin-2-one

To a mixture of diisopropylamine (1.86 g, 18.40 mmol) in THF (20 mL) wasadded n-BuLi (18.40 mmol, 8 mL) at −78° C. Then the reaction mixture wasstirred at rt for 0.51 h. DMPU (1.28 g, 18.36 mmol) was added andstirred at −78° C. for another I h. A solution of1-[(4-methoxyphenyl)methyl]-3-methyl-4-phenyl-piperazin-2-one (570 mg,1.84 mmol) in THF (20 mL) was added and stirred at −78° C. for 1 h. Theniodomethane (1.30 g, 9.18 mmol) was added in and stirred at rtovernight. The reaction mixture was quenched with NH₄Cl (aq), extractedwith DCM (100 mL×3), dried and concentrated. Further purification wascarried out by flash column eluting with PE/EA from 10/1 to 5/1 toafford 1-[(4-methoxyphenyl)methyl]-3,3-dimethyl-4-phenyl-piperazin-2-one(500 mg, 84%) as a colorless gum. ESI-MS (EI⁺, m/z): 325.0 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.31-7.18 (m, 4H), 7.16-7.06 (m, 3H), 6.90-6.84(m, 2H), 4.56 (s, 2H), 3.79 (s, 3H), 3.34-3.22 (m, 4H), 1.37 (s, 6H).

Step 7: 4-[(4-Methoxyphenyl)methyl]-2,2-dimethyl-1-phenyl-piperazine

To a solution of1-[(4-methoxyphenyl)methyl]-3,3-dimethyl-4-phenyl-piperazin-2-one (480mg, 1.48 mmol) in THF (3 mL) was added BH₃-THF (3 mL, 2.37 mmol) at rtand stirred at 70° C. for 5 h, then the reaction mixture was quenchedwith MeOH (3 mL). HCl (1 mL) was added and stirred at 70° C. for anotherI h. The reaction solution was concentrated, washed with water (30mL×3), extracted with EtOAc (30 mL×3), dried and concentrated. Furtherpurification was carried out by flash column eluting with PE/EA from10/1 to 5/1 to afford4-[(4-methoxyphenyl)methyl]-2,2-dimethyl-1-phenyl-piperazine (325 mg,71%) as a white solid. ESI-MS (EI⁺, m/z): 311.0 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.24-7.12 (m, 4H), 7.09-6.96 (m, 3H), 6.79 (d, J=8.6 Hz, 2H),3.73 (d, J=10.6 Hz, 3H), 3.44-3.31 (m, 2H), 3.23-3.00 (m, 2H), 2.59-2.38(m, 2H), 2.30-2.13 (m, 2H), 0.97 (s, 6H).

Step 8: 2,2-Dimethyl-1-phenyl-piperazine

To a mixture of4-[(4-methoxyphenyl)methyl]-2,2-dimethyl-1-phenyl-piperazine (310 mg,998 umol), ammonium formate (629 mg, 10 mmol) in MeOH (20 mL) was added10% Pd—C (100 mg, 998 umol), the reaction solution was stirred at 25° C.for 2 h. Then the mixture was filtered and concentrated, furtherpurification was carried out via silica gel chromatography eluting withDCM/MeOH from 20/1 to 5/1 to afford 2,2-dimethyl-1-phenyl-piperazine(132 mg, 69%) as a colorless gum. ESI-MS (EI⁺, m/z): 191.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.27-7.26 (m, 2H), 7.16-7.07 (m, 3H), 3.08 (m,2H), 3.04-2.98 (m, 2H), 2.79 (s, 2H), 1.05 (s, 6H).

Step 9:2-[4-[5-(3,3-Dimethyl-4-phenyl-piperazine-1-carbonyl)-2,4-dimethyl-anilino]-1-piperidyl]benzonitrile

Followed the amide coupling general EDCI/HOBT method to obtain2-(4-(5-(3,3-Dimethyl-4-phenylpiperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile1-119 as a white solid. ESI-MS (EI⁺, m/z): 522.2 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 7.69 (d, J=7.5 Hz, 1H), 7.59 (dd, J=11.9, 7.2 Hz, 1H),7.27 (t, J=7.7 Hz, 2H), 7.19 (d, J=8.3 Hz, 1H), 7.14-7.03 (m, 4H), 6.88(d, J=17.0 Hz, 1H), 6.44 (s, 1H), 4.55 (t, J=9.6 Hz, 1H), 4.03-3.37 (m,5H), 3.27-2.93 (m, 6H), 2.09 (dd, J=21.9, 16.2 Hz, 8H), 1.77-1.64 (m,2H), 1.23-0.84 (m, 6H).

Example 12:2-[4-[5-3,3-Dimethyl-4-(2-pyridyl)piperazine-1-carbonyl]-2,4-dimethyl-anilino]-1-piperidyl]benzonitrile,I-118

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: tert-Butyl-3,3-dimethyl-4-(2-pyridyl)piperazine-1-carboxylate

To a solution of tert-butyl-3,3-dimethylpiperazine-1-carboxylate (2.14g, 9.99 mmol) and 2-bromopyridine (1.58 g, 9.99 mmol) in dioxane (20 mL)was added Pd₂(dba)₃ (548 mg, 599 umol), BrettPhos (745 mg, 1.20 mmol),tBuONa (2.04 g, 29.96 mmol). The resulting mixture was stirred at 80° C.for 5 h. The mixture was filtered and concentrated, further purificationwas via silica gel chromatography eluting with PE/EA from 10/1 to 5/1 toobtain tert-butyl 3,3-dimethyl-4-(2-pyridyl)piperazine-1-carboxylate(621 mg, 21%) as a yellow solid. ESI-MS (EI⁺, m/z): 292.3 [M+H]⁺.

Step 2: 2,2-Dimethyl-1-(2-pyridyl)piperazine

A mixture oftert-butyl-3,3-dimethyl-4-(2-pyridyl)piperazine-1-carboxylate (621 mg,2.13 mmol) and HCl in dioxane (4 M, 3 mL, 12 mmol) was stirred at rt for2 h. The reaction mixture was concentrated, diluted with water (50mL×3), extracted with EtOAc (50 mL×3), washed with brine (50 mL×3),dried and concentrated. Further purification was carried out by aflash-column eluting with DCM/MeOH from 20/1 to 5/1 to obtain2,2-dimethyl-1-(2-pyridyl)piperazine (312 mg, 77%) as a yellow gum.ESI-MS (EI⁺, m/z): 192.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d,J=7.3 Hz, 1H), 7.50 (m, 1H), 6.92 (t, J=7.6 Hz, 1H), 6.84 (m, 1H),3.33-3.26 (m, 2H), 3.08-2.98 (m, 2H), 2.77 (s, 2H), 1.29 (s, 6H).

Step 3:2-[4-[5-[3,3-Dimethyl-4-(2-pyridyl)piperazine-1-carbonyl]-2,4-dimethyl-anilino]-1-piperidyl]benzonitrile

Followed the amide coupling general EDCI/HOBT method to obtain2-[4-[5-[3,3-dimethyl-4-(2-pyridyl)piperazine-1-carbonyl]-2,4-dimethyl-anilino]-1-piperidyl]benzonitrile,I-118, as a white solid. ESI-MS (EI⁺, m/z): 523.3 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.16 (dd, J=3.3 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.56(dt, J=7.7 Hz, 2H), 7.17 (dd, J=8.2 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H),6.93-6.84 (m, 2H), 6.83-6.69 (m, 1H), 6.43 (d, J=12.6 Hz, 1H), 4.55 (d,J=8.4 Hz, 1H), 3.87-3.37 (m, 7H), 3.28 (d, J=14.6 Hz, 2H), 2.95 (t,J=10.9 Hz, 2H), 2.07 (dd, J=11.1 Hz, 8H), 1.76-1.64 (m, 2H), 1.32 (m,6H).

Example 13:2-(4-(2,4-Dimethyl-5-(4-(2-oxoindolin-7-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile,I-61

Synthetic Scheme:

Procedures and Preparation:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: tert-Butyl 4-(1H-indol-7-yl)piperazine-1-carboxylate

Vinylmagnesium bromide (1 M in THF, 13 mL) and Et₂O (32.5 mL, 2.5 mlmmol⁻¹) were mixed in an oven dried flask and cooled to −40° C. under N₂with stirring. tert-Butyl 4-(2-nitrophenyl)piperazine-1-carboxylate (1g, 3.25 mmol) was dissolved in THF (8 mL) and added dropwise to theGrignard mixture. The solution was stirred at −40° C. for 4 hrs, andthen quenched with sat. aq. NH₄Cl. The aqueous layer was separated andextracted using EtOAc, the organic layer was dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by silica columnchromatography (silica, PE/EA=2/1) to yield the title compoundtert-butyl 4-(1H-indol-7-yl)piperazine-1-carboxylate (500 mg, 1.66 mmol,51%) as yellow solid. ESI-MS (EI⁺, m/z): 302.3 [M+H]⁺.

Step 2: tert-Butyl 4-(2-oxoindolin-7-yl)piperazine-1-carboxylate

To a 50 mL vial was added tert-butyl4-(1H-indol-7-yl)piperazine-1-carboxylate (410 mg, 1.36 mmol) int-butanol (12 mL) and water (5.5 mL). The solution was stirred at rt andthen NBS (242 mg, 1.36 mmol) was added, the reaction was allowed to stirat rt for 3 hrs. The reaction mixture was diluted with ethyl acetate andwashed with water. The organic layer was separated, washed with brineand dried over Na₂SO₄. The solvent was evaporated in vacuo and theresulting crude oil was purified via preparative HPLC to afford thedesired product tert-butyl 4-(2-oxoindolin-7-yl)piperazine-1-carboxylate(19.4 mg, 0.061 mmol, 5%) as white solid. ESI-MS (EI⁺, m/z): 318.2[M+H]⁺.

Step 3: 7-(Piperazin-1-yl)indolin-2-one

The mixture of tert-butyl 4-(2-oxoindolin-7-yl)piperazine-1-carboxylate(21 mg, 0.066 mmol) in TFA (0.5 mL) and DCM (2 mL) was stirred at rt for2 hrs. The reaction mixture was concentrated to give crude product7-(piperazin-1-yl)indolin-2-one as yellow solid that directly used forthe next step. ESI-MS (EI⁺, m/z): 218.3 [M+H]⁺.

Following the amide coupling general EDCI/HOBT method to obtain2-(4-(2,4-Dimethyl-5-(4-(2-oxoindolin-7-yl) piperazine-1-carbonyl)phenylamino) piperidin-1-yl) benzonitrile 1I-61 as a white solid.

¹H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 7.57 (dd, J=7.5, 1.5 Hz, 1H),7.53-7.45 (m, 1H), 7.07-6.97 (m, 4H), 6.96-6.90 (m, 2H), 6.51 (s, 1H),4.02 (s, 2H), 3.72-3.32 (m, 8H), 3.08-2.90 (m, 4H), 2.84 (s, 2H),2.30-2.18 (m, 5H), 2.13 (s, 3H), 1.84-1.60 (m, 2H). ESI-MS (EI⁺, m/z):549.3 [M+H]⁺.

Example 14:2-(4-(5-(4-(1H-Pyrazolo[4,3-c]pyridin-7-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-44

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1:7-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine

To a solution of 7-bromo-1H-pyrazolo[4,3-c]pyridine (500 mg, 2.52 mmol)in DMF (20 mL) was added NaH (100.80 mg, 2.52 mmol, 60% purity) slowlyat 0° C. The mixture was stirred at 0° C. for 2 h. The reaction mixturewas quenched with saturated aqueous NH₄Cl solution (10 mL). Then themixture was diluted with EtOAc and washed with water and brine. Theorganic phase was dried and concentrated. The residue was purified bycolumn chromatography (PE:EA=3:1) to give (620 mg, 827 umol, 66% yield)as a yellow liquid. ESI-MS (EI⁺, m/z): 328.0 [M+H]⁺.

Step 2:7-(Piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine

7-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine(328 mg, 999.15 umol), piperazine (172.13 mg, 2 mmol), Pd₂(dba)₃ (91.49mg, 99.92 umol), BINAP (62.21 mg, 99.92 umol) and tBuONa (192.04 mg, 2mmol) were dissolved in toluene (5 mL). The mixture was stirred under N₂at 80° C. for 16 h. The mixture was purified via preparative HPLC toafford 7-(piperazin-1-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazolo [4,3-c] pyridine (220 mg, 660 umol, 66% yield) as ayellow oil. ESI-MS (EI⁺, m/z): 333.9 [M+H]⁺.

Step 3:2-(4-(2,4-Dimethyl-5-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-7-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile

Followed the amide coupling HATU method to obtain the crude and purifiedby SGC (PE:EA=1:1) to obtain the product (80 mg, 106 umol, 75% yield) asa yellow solid. ESI-MS (EI⁺, m/z): 665.3 [M+H]⁺.

Step 4:2-(4-(5-(4-(1H-Pyrazolo[4,3-c]pyridin-7-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

A solution of2-(4-(2,4-dimethyl-5-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-7-yl)piperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile(70 mg, 105.28 umol) in TBAF (1 M, 3 mL) was stirred at 70° C. for 16 h.The mixture was purified via preparative HPLC to afford2-(4-(5-(4-(1H-pyrazolo[4,3-c]pyridin-7-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrileI-44 (33.2 mg, 62 umol, 59% yield) as a white solid. ¹H NMR (500 MHz,CDCl₃) δ 8.86 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.56 (d, J=7.5 Hz,1H), 7.48 (t, J=8.0 Hz, 1H), 7.06-6.97 (m, 2H), 6.92 (s, 1H), 6.49 (s,1H), 4.04 (d, J=16.0 Hz, 2H), 3.61 (d, J=10.0 Hz, 1H), 3.54-3.39 (m,4H), 3.32 (s, 2H), 3.13 (s, 2H), 3.03-2.87 (m, 2H), 2.26-2.16 (m, 5H),2.12 (s, 3H), 1.72-1.58 (m, 2H). LCMS Method (10 mM Ammonium hydrogencarbonate) Tr=2.10 min ESI-MS (EI⁺, m/z): 535.3 [M+H]⁺.

Example 15:2-((1-(2-Cyanophenyl)piperidin-4-yl)(2,4-dimethyl-5-(4-(2-sulfamoylphenyl)piperazine-1-carbonyl)phenyl)amino)acetamide,I-27

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 2-((1-(2-Cyanophenyl)piperidin-4-yl)(5-(methoxycarbonyl)-2,4-dimethylphenyl)amino)acetic Acid

To a solution of methyl5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate (1.17 g,3.22 mmol) in DMF (10 mL) at 15° C. was added tBuONa (928.33 mg, 9.66mmol) followed by tert-butyl 2-bromoacetate (3.14 g, 16.10 mmol). Thenthe mixture was stirred at 90° C. for 16 h. The mixture was purified bychromatography (silica, ethyl acetate/petroleum ether=1/1) to afford2-((1-(2-cyanophenyl)piperidin-4-yl)(5-(methoxycarbonyl)-2,4-dimethylphenyl)amino)aceticacid (600 mg, 1.42 mmol, 44% yield) as a brown solid. ESI-MS (EI⁺, m/z):422.3 [M+H]⁺.

Step 2: Methyl 5-((2-amino-2-oxoethyl) (1-(2-cyanophenyl)piperidin-4-yl) amino)-2,4-dimethylbenzoate

2-((1-(2-cyanophenyl)piperidin-4-yl)(5-(methoxycarbonyl)-2,4-dimethylphenyl)amino)aceticacid (421 mg, 998.84 umol), HATU (489.88 mg, 1.30 mmol), DIPEA (645.45mg, 4.99 mmol, 872.23 uL) and NH₄Cl (106.86 mg, 2 mmol) were dissolvedin DMF (6 mL). The mixture was stirred at 15° C. for 3 h. The reactionmixture was purified via preparative HPLC to afford methyl5-((2-amino-2-oxoethyl)(1-(2-cyanophenyl)piperidin-4-yl)amino)-2,4-dimethylbenzoate(260 mg, 618 umol, 62% yield) as a white solid. ESI-MS (EI⁺, m/z): 421.3[M+H]⁺.

Step 3: 5-((2-Amino-2-oxoethyl) (1-(2-cyanophenyl) piperidin-4-yl)amino)-2,4-dimethylbenzoic Acid

To a solution of methyl5-((2-amino-2-oxoethyl)(1-(2-cyanophenyl)piperidin-4-yl)amino)-2,4-dimethylbenzoate(100 mg, 237.81 umol) in DCM (2 mL) at 0° C. was added BBr₃ (237.81umol, 2 mL, 17% purity). Then the mixture was stirred at 0-15° C. for 2h. The mixture was quenched with MeOH (2 mL) at 0° C., and thenconcentrated in vacuo. The residue was directly used for the next step.ESI-MS (EI⁺, m/z): 407.3 [M+H]⁺.

Step 4:2-((1-(2-Cyanophenyl)piperidin-4-yl)(2,4-dimethyl-5-(4-(2-sulfamoylphenyl)piperazine-1-carbonyl)phenyl)amino)acetamide

Followed the amide coupling EDCI/HOBT method to obtain2-((1-(2-cyanophenyl)piperidin-4-yl)(2,4-dimethyl-5-(4-(2-sulfamoylphenyl)piperazine-1-carbonyl)phenyl)amino)acetamide1-27 as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.02 (dd, J=8.0, 1.0Hz, 1H), 7.62-7.57 (m, 1H), 7.53 (dd, J=8.0, 1.0 Hz, 1H), 7.48-7.38 (m,2H), 7.34 (t, J=7.5 Hz, 1H), 7.13 (s, 1H), 7.03-6.92 (m, 3H), 6.66 (s,1H), 5.61 (s, 2H), 5.52 (s, 1H), 3.82-3.68 (m, 2H), 3.59 (d, J=12.0 Hz,2H), 3.46 (s, 1H), 3.40 (s, 1H), 3.29-2.86 (m, 5H), 2.82-2.63 (m, 2H),2.38 (s, 3H), 2.30 (s, 3H), 1.99-1.76 (m, 4H).

ESI-MS (EI⁺, m/z): 630.3 [M+H]⁺.

Example 16:(R)-2-(4-(5-(4-(5-Fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-116

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1:(R)-2-(4-(5-(3-((tert-Butyldimethylsilyloxy)methyl)-4-(5-fluoropyridin-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

(R)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(200 mg, 355.98 umol), 2-bromo-5-fluoropyridine (125.30 mg, 711.96umol), tBuONa (68.42 mg, 711.96 umol) andbis(tri-tert-butylphosphine)palladium (36.38 mg, 71.20 umol) weredissolved in toluene (5 mL). The mixture was stirred under N₂ at 80° C.for 16 h. The mixture was concentrated in vacuo. The residue wasdissolved in EtOAc (100 mL) and washed with H₂O (100 mL×2). The layerswere separated, The EtOAc extracts were dried (Na₂SO₄), filtered andconcentrated under vacuum to afford the crude product(R)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)-4-(5-fluoropyridin-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(200 mg, crude) as a yellow oil which was used for the next step withoutfurther purification. ESI-MS (EI⁺, m/z): 657.3 [M+H]⁺.

Step 2:(R)-2-(4-(5-(4-(5-fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

(R)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)-4-(5-fluoropyridin-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(200 mg, 304.46 umol) and TBAF (1 M, 2 mL) were dissolved in THF (2 mL).The mixture was stirred at 20° C. for 2 h. The mixture was purified viapreparative HPLC to afford(R)-2-(4-(5-(4-(5-fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrileI-116 (67 mg, 123 umol, 41% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.06-7.94 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.8 Hz,1H), 7.35-7.22 (m, 1H), 7.09-6.88 (m, 3H), 6.69-6.58 (m, 1H), 6.56-6.32(m, 1H), 4.90-4.22 (m, 2H), 3.86 (d, J=11.6 Hz, 1H), 3.81-3.37 (m, 9H),3.37-3.14 (m, 2H), 3.09-2.87 (m, 3H), 2.34-2.05 (m, 8H). ESI-MS (EI⁺,m/z): 543.3 [M+H]⁺.

Example 17:(R)-2-(4-(5-(4-(3-Fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-115

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

The procedure was the same as example 16.

¹H NMR (400 MHz, CDCl₃) δ 7.98-7.88 (m, 1H), 7.56 (d, J=7.6 Hz, 1H),7.48 (t, J=8.0 Hz, 1H), 7.34-7.20 (m, 1H), 7.11-6.86 (m, 3H), 6.86-6.75(m, 1H), 6.60-6.31 (m, 1H), 4.80-4.50 (m, 1H), 4.48-3.84 (m, 4H),3.76-3.21 (m, 9H), 3.08-2.86 (m, 2H), 2.34-2.05 (m, 8H).

ESI-MS (EI⁺, m/z): 543.3 [M+H]⁺.

Example 18:(R)-2-(4-(5-(4-(4-Fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-99

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

The procedure was same as example 16.

¹H NMR (400 MHz, CDCl₃) δ 8.14-8.00 (m, 1H), 7.56 (d, J=7.6 Hz, 1H),7.48 (t, J=7.6 Hz, 1H), 7.08-6.87 (m, 3H), 6.60-6.23 (m, 3H), 4.92-4.18(m, 2H), 3.97-3.84 (m, 1H), 3.82-3.37 (m, 9H), 3.35-2.88 (m, 4H),2.31-2.07 (m, 8H).

ESI-MS (EI⁺, m/z): 543.3 [M+H]⁺.

Example 19:(S)-2-(4-(5-(4-(4-Fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-100

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

The procedure was same as example 16.

¹H NMR (500 MHz, CDCl₃) δ 8.14-8.00 (m, 1H), 7.56 (d, J=7.5 Hz, 1H),7.48 (t, J=7.5 Hz, 1H), 7.08-6.87 (m, 3H), 6.58-6.23 (m, 3H), 4.90-4.22(m, 2H), 3.97-3.84 (m, 1H), 3.82-3.37 (m, 9H), 3.35-2.88 (m, 4H),2.31-2.07 (m, 8H).

ESI-MS (EI⁺, m/z): 543.3 [M+H]⁺.

Example 20:(R)-2-(4-(5-(3-(Hydroxymethyl)-4-isopropylpiperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-114

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: (R)-Benzyl 3-(hydroxymethyl)-4-isopropylpiperazine-1-carboxylate

(R)-Benzyl3-((tert-butyldimethylsilyloxy)methyl)piperazine-1-carboxylate (365 mg,1 mmol), 2-iodopropane (1.70 g, 10 mmol) and K₂CO₃ (414.63 mg, 3 mmol)were dissolved in DMF (4 mL). The mixture was stirred at 85° C. for 16h. The mixture was purified via preparative HPLC to afford (R)-benzyl3-(hydroxymethyl)-4-isopropylpiperazine-1-carboxylate (200 mg, 684 umol,68% yield) as a colorless oil. ESI-MS (EI⁺, m/z): 293.3 [M+H]⁺.

Step 2: (R)-(1-Isopropylpiperazin-2-yl)methanol

(R)-Benzyl 3-(hydroxymethyl)-4-isopropylpiperazine-1-carboxylate (200mg, 684.06 umol) and Pd/C (16.62 mg, 136.81 umol) were dissolved in MeOH(10 mL). The mixture was stirred under H₂ at 20° C. for 16 h. Themixture was filtered and concentrated to afford a colorless oil that wasused directly in the next step.

Step 3:(R)-2-(4-(5-(3-(Hydroxymethyl)-4-isopropylpiperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

Followed the amide coupling HATU method to obtain(R)-2-(4-(5-(3-(hydroxymethyl)-4-isopropylpiperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrileI-114 as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=7.6 Hz,1H), 7.49 (t, J=7.6 Hz, 1H), 7.06-6.97 (m, 2H), 6.90 (d, J=2.8 Hz, 1H),6.45 (d, J=7.6 Hz, 1H), 4.52-3.92 (m, 1H), 3.91-3.10 (m, 10H), 3.04-2.35(m, 6H), 2.28-2.05 (m, 9H), 1.14 (q, J=6.5 Hz, 3H), 1.03-0.92 (m, 3H).

ESI-MS (EI⁺, m/z): 490.3 [M+H]⁺.

Example 21:(S)-2-(4-(5-(3-(Hydroxymethyl)-4-isopropylpiperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-95

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

The procedure was same as example 20.

¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz,1H), 7.06-6.97 (m, 2H), 6.90 (d, J=2.8 Hz, 1H), 6.45 (d, J=7.6 Hz, 1H),4.52-3.92 (m, 1H), 3.91-3.10 (m, 10H), 3.04-2.35 (m, 6H), 2.28-2.05 (m,9H), 1.14 (q, J=6.5 Hz, 3H), 1.03-0.92 (m, 3H). ESI-MS (EI⁺, m/z): 490.3[M+H]⁺.

Example 22:(S)-2-(4-(5-(3-(Hydroxymethyl)-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-98

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: (S)-4-(Benzyloxycarbonyl)piperazine-2-carboxylic Acid

To solution of (2S)-piperazine-2-carboxylic acid (10 g, 76.84 mmol) andNaOH (9.22 g, 230.52 mmol) in H₂O (50 mL) was added a solution of cupricsulfate pentahydrate (9.61 g, 38.42 mmol) in water (10 ml) at 30° C.After cooling to 0° C., NaHCO₃ (7.75 g, 92.21 mmol) was added followedby the dropwise addition of benzyl chloroformate (13.11 g, 76.84 mmol).The reaction mixture was stirred at 0° C. for 3 h and then at rtovernight. The N-Cbz-Lys-Cu2+-complex precipitate was collected andwashed with water (20 mL) and acetone (10 mL), then dried. To a boilingsuspension of EDTA (24.70 g, 84.52 mmol) in water (80 mL), the powderedN-Cbz-Lys-Cu2+ complex was added portionwise, while the pH wasmaintained at 7.0 by addition of conc. HCl (5 mL). The white precipitatewas collected, washed with water and methanol and dried. The product wasrecrystallized from ethanol-water to afford(2S)-4-benzyloxycarbonylpiperazine-2-carboxylic acid (12 g, 45.41 mmol)as a white solid. MS (EI⁺, m/z): 265.0 [M+H]⁺.

Step 2:(S)-4-(Benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylicAcid

(2S)-4-Benzyloxycarbonylpiperazine-2-carboxylic acid (12 g, 45.41 mmol)and tert-butoxycarbonyl tert-butyl carbonate (19.82 g, 90.82 mmol) weredissolved in THF (50 mL), followed by addition of NaHCO₃(15.26 g, 181.64mmol) in H₂O (50 mL). The solution was stirred at 20° C. for 10 h. Thereaction mixture was extracted with ether (100 mL). The layers wereseparated, and to the aqueous phase was added 1 N HCl (182 mL) to adjustthe pH to 3. The aqueous layer was extracted with DCM (100 mL×3). Thecombined DCM extracts were dried (Na₂SO₄), filtered and concentratedunder vacuum. The residue was purified by recrystallization to afford(S)-4-(benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylicacid (15 g, 41.16 mmol) as a white solid. MS (EI⁺, m/z): 309.0 [M+H]⁺.

Step 3: (S)-4-Benzyl 1-tert-butyl2-methylpiperazine-1,2,4-tricarboxylate

(S)-4-(Benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylicacid (6.60 g, 19.92 mmol) was dissolved in DMF (30 mL), followed by theaddition of MeI (2.83 g, 19.92 mmol) and K₂CO₃ (5.51 g, 39.83 mmol). Thesolution was stirred at rt for 2 h. The mixture was diluted by H₂O (100ml) and extracted with EtOAc (100 ml×3). The combined organic phase waswashed with brine, dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified by chromatography (silica, ethyl acetate/petroleumether=1/10 as eluent) to give the desire product (S)-4-benzyl1-tert-butyl 2-methylpiperazine-1,2,4-tricarboxylate (4.50 g, 13.03mmol) as a yellow oil. MS (EI⁺, m/z): 279.2 [M+H]⁺.

Step 4: (S)-4-Benzyl 1-tert-butyl2-(hydroxymethyl)piperazine-1,4-dicarboxylate

(S)-4-Benzyl 1-tert-butyl 2-methylpiperazine-1,2,4-tricarboxylate (2.90g, 7.66 mmol) was dissolved in THF (30 mL) in an ice bath, followed bythe addition of LiBH₄ in THF (1.31 g, 60 mmol). The solution was stirredat rt for 14 h. The reaction mixture was quenched by aq. NH₄Cl (20 mL).The layers were separated. The aqueous layer was extracted with EtOAc(50 mL). The combined EtOAc extracts were dried (Na₂SO₄), filtered andconcentrated under vacuum. The residue was purified by chromatography(silica, ethyl acetate/petroleum ether=1/5) to afford (S)-4-benzyl1-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (2.10 g, 5.99mmol) as a white oil. MS (EI⁺, m/z): 251.2 [M+H]⁺.

Step 5:(S)-2-(4-(5-(3-(Hydroxymethyl)-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

(S)-2-(4-(5-(3-((tert-Butyldimethylsilyloxy)methyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(561 mg, 0.10 mmol) was dissolved in DMF (30 mL), followed by theaddition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (696 mg, 0.30mmol) and K₂CO₃ (41.4 mg, 0.30 mmol). The mixture was heated to 120° C.for 14 h. The reaction mixture was filtered and purified via preparativeHPLC to afford(S)-2-(4-(5-(3-(hydroxymethyl)-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile1-98 as a white solid. MS (EI⁺, m/z): 530.3 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.69 (dd, J=7.6, 1.5 Hz, 1H), 7.64-7.52 (m, 1H), 7.18 (d,J=8.3 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.85 (d, J=5.5 Hz, 1H), 6.37 (s,1H), 4.74 (d, J=91.9 Hz, 1H), 4.59-4.44 (m, 1H), 3.97 (d, J=79.0 Hz,1H), 3.70-3.39 (m, 6H), 2.96 (t, J=11.1 Hz, 3H), 2.71 (d, J=73.7 Hz,2H), 2.08 (s, 3H), 2.03 (s, 5H), 1.69 (d, J=10.0 Hz, 2H).

Example 23:(R)-2-(4-(5-(3-(Hydroxymethyl)-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile, I-96

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

The procedure is the same as that used for example 22.

MS (EI⁺, m/z): 530.3 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.69 (dd,J=7.7, 1.4 Hz, 1H), 7.59 (dd, J=11.5, 4.3 Hz, 1H), 7.18 (d, J=8.3 Hz,1H), 7.07 (t, J=7.5 Hz, 1H), 6.85 (d, J=5.6 Hz, 1H), 6.37 (s, 1H), 4.74(d, J=90.3 Hz, 1H), 4.61-4.42 (m, 1H), 3.97 (d, J=77.9 Hz, 1H),3.72-3.40 (m, 6H), 3.15 (d, J=39.4 Hz, 3H), 2.96 (t, J=11.3 Hz, 3H),2.71 (d, J=74.3 Hz, 2H), 2.08 (s, 3H), 2.03 (s, 5H), 1.68 (d, J=9.2 Hz,2H).

Example 24:2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)-4,5-difluorobenzenesulfonamide,I-104

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 2-Amino-4,5-difluorobenzenesulfonic Acid

A mixture of 3,4-difluoroaniline (20 g, 154.91 mmol) and chlorosulfonicacid (60 mL) was stirred at 140° C. for 17 h. The reaction mixture wasused for the next step directly. MS (EI⁺, m/z): 209.9 [M+H]⁺.

Step 2: 2-Amino-4,5-difluorobenzene-1-sulfonyl Chloride

To the mixture of step 1 was added thionyl chloride (60 mL) and theresulting mixture was stirred at 70° C. for 17 h. The reaction mixturewas poured into water (400 mL) slowly. The aqueous layer was extractedwith Et₂O (400 mL×2). The combined organic layers were dried (Na₂SO₄),filtered and concentrated under vacuum to obtain2-amino-4,5-difluoro-benzenesulfonyl chloride (33 g, 72.49 mmol, 47%yield, 50% purity) as a dark oil. MS (EI⁺, m/z): 227.9 [M+H]⁺.

Step 3: 2-Amino-4,5-difluorobenzenesulfonamide

To a mixture of 2-amino-4,5-difluoro-benzenesulfonyl chloride (33 g,72.49 mmol) and 1,4-dioxane (400 mL) was added aqueous ammoniumhydroxide solution (300.02 mL) at 20° C. The resulting mixture wasstirred at 20° C. for 3 h. 1,4-Dioxane was removed by evaporation. Theaqueous layer was extracted with EtOAc (400 mL×2). The combined organiclayers were dried (Na₂SO₄), filtered and concentrated under vacuum. Theresidue was purified by chromatography (silica, ethyl acetate/petroleumether=1/1) to afford 2-amino-4,5-difluoro-benzenesulfonamide (5.50 g,23.78 mmol, 33% yield, 90% purity) as a black solid. MS (EI⁺, m/z):208.9 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.49 (dd, J=10.8, 9.0 Hz, 1H),7.40 (s, 2H), 6.77 (dd, J=13.0, 6.9 Hz, 1H), 5.97 (s, 2H). The sulfonylamide position was confirmed by COSY and NOESY spectrum.

Step 4: 4,5-Difluoro-2-(piperazin-1-yl)benzenesulfonamide

A mixture of 2-amino-4,5-difluoro-benzenesulfonamide (1.04 g, 5 mmol),2-bromo-N-(2-bromoethyl)ethanamine hydrobromide (15.59 g, 50 mmol) andn-butyl alcohol (50 mL) was stirred at 120° C. for 40 h. The reactionmixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified via preparative HPLC to afford4,5-difluoro-2-piperazin-1-yl-benzenesulfonamide (400 mg, 1.15 mmol, 23%yield, 80% purity) as a white solid. MS (EI⁺, m/z): 278.1 [M+H]⁺.

Step 5:2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)-4,5-difluorobenzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-[4-[5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]-4,5-difluoro-benzenesulfonamide1-104 as a white solid. MS (EI⁺, m/z): 609.3 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.85-7.77 (m, 2H), 7.70-7.68 (m, 1H), 7.61-7.57 (m, 1H),7.17-7.16 (m, 3H), 7.09-7.06 (m, 1H), 6.87 (s, 1H), 6.44 (s, 1H),4.56-4.54 (m, 1H), 3.84 (br, 2H), 3.52-3.49 (m, 3H), 3.39-3.37 (m, 2H),2.99-2.92 (m, 4H), 2.83-2.78 (m, 2H), 2.09 (s, 6H), 2.05-2.03 (m, 2H),1.71 (br, 2H).

Example 25: Synthesis of2-(4-(6-(1-(2-cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpicolinoyl)piperazin-1-yl)-5-fluorobenzenesulfonamide,I-103

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 4-Fluorophenylcarbamoylsulfamoyl Chloride

To a solution of N-(oxomethylene) sulfamoyl chloride (5.67 g, 40.05mmol) in nitroethane (80 mL) was added 4-fluoroaniline (4.45 g, 40.05mmol) at −42° C. The resulting mixture was stirred at −42° C. for 1 h.The reaction mixture was used for the next step directly. MS (EI⁺, m/z):155.1 [M-SO₂Cl+H]⁺.

Step 2: 7-Fluoro-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide

A mixture of N-[(4-fluorophenyl) carbamoyl] sulfamoyl chloride (10.11 g,40 mmol), AlCl₃ (6.13 g, 46 mmol) and nitroethane (80 mL) was stirred at110° C. for 1 h. The reaction mixture was poured into water (200 mL).The aqueous layer was extracted with EtOAc (150 mL×2). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure to obtain7-fluoro-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide (7.50g, 22.20 mmol, 56% yield, 64% purity) as a yellow solid. MS (EI⁺, m/z):216.9 [M+H]⁺.

Step 3: 2-Amino-5-fluorobenzenesulfonamide

Conc. sulfuric acid (75 mL) was added slowly to a mixture of7-fluoro-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide (7.50g, 22.20 mmol) in water (75 mL). The resulting mixture was stirred at140° C. for 2 h. The reaction mixture was diluted with water (200 mL).The aqueous layer was neutralized with 40% aqueous NaOH solution (about100 mL) and extracted with EtOAc (500 mL×2). The combined organic layerswere dried (Na₂SO₄), filtered and concentrated under reduced pressure.The residue was purified by chromatography (silica, ethylacetate/petroleum ether=1/1) to afford2-amino-5-fluoro-benzenesulfonamide (3.70 g, 18.48 mmol, 83% yield, 95%purity) as a brown solid. MS (EI⁺, m/z): 191.0 [M+H]⁺.

Step 4: 5-Fluoro-2-(piperazin-1-yl)benzenesulfonamide

A mixture of 2-amino-5-fluoro-benzenesulfonamide (950 mg, 4.99 mmol),2-bromo-N-(2-bromoethyl) ethanamine hydrobromide (7.78 g, 24.95 mmol)and n-butyl alcohol (50 mL) was stirred at 120° C. for 24 h. Thereaction mixture was allowed to cool to rt. Filtered and the filtratewas used for the next step directly. MS (EI⁺, m/z): 260.2 [M+H]⁺.

Step 5: tert-Butyl4-(4-fluoro-2-sulfamoylphenyl)piperazine-1-carboxylate

A mixture of 5-fluoro-2-piperazin-1-yl-benzenesulfonamide (12.71 g, 49mmol), Boc₂O (53.47 g, 245 mmol), sodium carbonate (31.16 g, 294 mmol),and n-butyl alcohol (49.02 mL) in water (149.99 mL) was stirred at 20°C. for 17 h. n-BuOH was removed by evaporation. The aqueous layer wasextracted with EtOAc (50 mL×2). The combined EtOAc extracts were dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residuewas purified by chromatography (silica, ethyl acetate/petroleumether=1/5) to afford 3.5 g crude product. The crude product was purifiedvia preparative HPLC to afford 350 mg crude product. This crude productwas purified by Prep-TLC to afford tert-butyl4-(4-fluoro-2-sulfamoyl-phenyl)piperazine-1-carboxylate (170 mg, 132.16umol, 1% yield, 95% purity) as a white solid. MS (EI⁺, m/z): 360.1[M+H]⁺.

Step 6: 5-Fluoro-2-(piperazin-1-yl)benzenesulfonamide Hydrochloride

A mixture of tert-butyl4-(4-fluoro-2-sulfamoyl-phenyl)piperazine-1-carboxylate (120 mg, 333.87umol) and 4 M HCl in dioxane (4.17 mL) was stirred at 25° C. for 1 h.The reaction mixture was concentrated under reduced pressure to give5-fluoro-2-piperazin-1-yl-benzenesulfonamide hydrochloride (95 mg,317.99 umol, 95% yield, and 99% purity) as a white solid. MS (EI⁺, m/z):260.2 [M+H]⁺.

Step 7: 5-Fluoro-2-(piperazin-1-yl)benzenesulfonamide Hydrochloride

Following the amide coupling EDCI/HOBT method to afford2-[4-[6-[[1-(2-cyanophenyl)-4-piperidyl]amino]-3,5-dimethyl-pyridine-2-carbonyl]piperazin-1-yl]-5-fluoro-benzenesulfonamideI-103 as a white solid. MS (EI⁺, m/z): 592.3 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.70-7.68 (m, 1H), 7.67-7.53 (m, 3H), 7.47-7.43 (m, 1H),7.17-7.13 (m, 4H), 7.09-7.06 (m, 1H), 5.64-5.63 (m, 1H), 4.04 (br, 1H),3.85 (br, 2H), 3.51-3.49 (m, 2H), 3.40-3.38 (m, 2H), 2.95-2.89 (m, 4H),2.83 (br, 2H), 2.07 (s, 3H), 2.06 (s, 3H), 2.01-1.99 (m, 2H), 1.79-1.71(m, 2H).

Example 26: Synthesis of2-(4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-4-fluoro-2-methylbenzoyl)piperazin-1-y)benzenesulfonamide,I-90

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 4-Fluoro-5-iodo-2-methylbenzoic Acid

4-Fluoro-2-methyl-benzoic acid (11 g, 71.36 mmol) was dissolved in TFA,and the reaction mixture was stirred at 5° C. upon which the NIS (16.86g, 74.93 mmol) was added in portions. Then the temperature was warmed to60° C. for 3 h. The reaction mixture was poured into ice water and aprecipitate appeared. After filtration of the mixture, the precipitatewas triturated with n-hexane to give 4-fluoro-5-iodo-2-methylbenzoicacid (6 g, 21.43 mmol, 30% yield) as a pink solid. MS (EI⁻, m/z): 278.9[M−H]⁻.

Step 2: Methyl 4-fluoro-5-iodo-2-methylbenzoate

4-Fluoro-5-iodo-2-methyl-benzoic acid (6 g, 21.43 mmol) was dissolved ina solution of 3 M HCl in MeOH (50 mL) and the reaction mixture wasstirred at 70° C. for 12 h. The reaction mixture was concentrated underreduced pressure to give methyl 4-fluoro-5-iodo-2-methylbenzoate (3.10g, 10.54 mmol, 49% yield) as a yellow solid which was used for the nextstep without further purification. MS (EI⁺, m/z): 295.0 [M+H]⁺.

Step 3: Methyl5-(1-(2-cyanophenyl)piperidin-4-ylamino)-4-fluoro-2-methylbenzoate

A mixture of methyl 4-fluoro-5-iodo-2-methyl-benzoate (1 g, 3.40 mmol),2-(4-amino-1-piperidyl)benzonitrile (1.03 g, 5.10 mmol), Pd₂(dba)₃(311.34 mg, 340 umol), BrettPhos (365 mg, 680 umol), and CS₂CO₃ (2.22 g,6.80 mmol) in toluene (17 mL) was stirred at 110° C. for 1.5 h under anitrogen atmosphere. The resulting mixture was partitioned between EtOAc(150 mL) and water (100 mL). The layers were separated. The aqueouslayer was extracted with EtOAc (150 mL). The combined EtOAc extractswere dried (Na₂SO₄), filtered and concentrated under reduced pressure.The residue was purified by chromatography (silica, ethylacetate/petroleum ether=1/10) to afford methyl5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-4-fluoro-2-methyl-benzoate (800mg, 1.96 mmol, 58% yield, 90% purity) as a yellow oil. MS (EI⁺, m/z):368.0 [M+H]⁺.

Step 4: 5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-4-fluoro-2-methylbenzoic Acid

A mixture of methyl5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-4-fluoro-2-methyl-benzoate (760mg, 2.07 mmol), lithium hydroxide monohydrate (1.74 g, 41.40 mmol) inTHF (21 mL) and water (21 mL) was stirred at 60° C. for 18 h. THF wasremoved by evaporation. Water (30 mL) was added. The aqueous layer wasextracted with DCM (50 mL). The DCM layer was discarded. The obtainedaqueous layer was acidified with 1 N HCl to pH 5 and extracted with2-methyltetrahydrofuran (50 mL×2). The combined 2-methyltetrahydrofuranlayers were dried (Na₂SO₄), filtered and concentrated under reducedpressure to give5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-4-fluoro-2-methyl-benzoic acid(670 mg, 1.71 mmol, 82% yield, 90% purity) as a yellow solid. MS (EI⁺,m/z): 354.0 [M+H]⁺.

Step 5: 2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-4-fluoro-2-methylbenzoyl)piperazin-1-yl)benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-[4-[5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-4-fluoro-2-methyl-benzoyl]piperazin-1-yl]benzenesulfonamide1-90 as a light-yellow solid. MS (EI⁺, m/z): 577.3 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 7.88-7.86 (m, 1H), 7.70-7.68 (m, 1H), 7.64-7.55 (m, 3H),7.37-7.33 (m, 1H), 7.18-7.16 (m, 1H), 7.09-7.05 (m, 1H), 6.98-6.95 (m,3H), 6.66-6.64 (m, 1H), 5.28-5.26 (m, 1H), 3.94-3.73 (m, 2H), 3.56-3.45(m, 3H), 3.41-3.36 (m, 2H), 3.10-2.76 (m, 7H), 2.12 (s, 3H), 2.02-2.00(m, 2H), 1.72-1.67 (m, 2H).

Example 27:2-(4-(3,5-Dimethyl-6-(4-(2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)pyridin-2-ylamino)piperidin-1-yl)benzonitrile,I-126

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1:2-(4-(6-Bromo-3,5-dimethylpyridin-2-ylamino)piperidin-1-yl)benzonitrile

A mixture of 2-(4-amino-1-piperidyl)benzonitrile (3 g, 14.91 mmol),2,6-dibromo-3,5-dimethyl-pyridine (4.74 g, 17.89 mmol), tBuONa (2.15 g,22.36 mmol), Pd₂ (dba)₃ (136.53 mg, 149.05 umol) and BINAP (278.43 mg,447.16 umol) in toluene (50 mL) was stirred at 80° C. for 17 h. Themixture was filtered and purified by silica gel chromatography to afford2-(4-(6-bromo-3,5-dimethylpyridin-2-ylamino)piperidin-1-yl)benzonitrile(2.10 g, 5.45 mmol, 36.55% yield) as product. ESI-MS (EI⁺, m/z): 385.1[M+H]⁺.

Step 2:2-(4-(3,5-Dimethyl-6-vinylpyridin-2-ylamino)piperidin-1-yl)benzonitrile

A mixture of2-(4-(6-bromo-3,5-dimethylpyridin-2-ylamino)piperidin-1-yl)benzonitrile(2.10 g, 5.45 mmol), potassium vinyltrifluoroborate (1.10 g, 8.18 mmol),K₂CO₃ (1.51 g, 10.90 mmol) and Pd(dppf)Cl₂ (199.40 mg, 272.50 umol) inH₂O (5 mL) and CH₃CN (20 mL) was stirred at 80° C. for 17 h. The mixturewas washed with water and extracted with EtOAc (100 mL). The organiclayer was purified by SGC to obtain2-(4-(3,5-dimethyl-6-vinylpyridin-2-ylamino)piperidin-1-yl)benzonitrile(1.20 g, 3.61 mmol, 66.23% yield). ESI-MS (EI⁺, m/z): 333.3 [M+H]⁺.

Step 3:2-(4-(6-Formyl-3,5-dimethylpyridin-2-ylamino)piperidin-1-yl)benzonitrile

A mixture of2-(4-(3,5-dimethyl-6-vinylpyridin-2-ylamino)piperidin-1-yl)benzonitrile(1.20 g, 3.61 mmol), K₂OsO₄ (66.42 mg, 180.50 umol) and NMO (845.82 mg,7.22 mmol) in H₂O (20 mL) and acetone (40 mL) was stirred at 20° C. for16 h. The mixture was extracted with EtOAc and purified by SGC to obtain2-(4-(6-formyl-3,5-dimethylpyridin-2-ylamino)piperidin-1-yl)benzonitrile(1 g, 2.99 mmol, 82.83% yield) as product. ESI-MS (EI⁺, m/z): 335.3[M+H]⁺.

Step 4:6-[[1-(2-Cyanophenyl)-4-piperidyl]amino]-3,5-dimethyl-pyridine-2-carboxylicAcid

A mixture of2-[4-[(6-formyl-3,5-dimethyl-2-pyridyl)amino]-1-piperidyl]benzonitrile(350 mg, 1.05 mmol), 2-methyl-2-butene (147.27 mg, 2.10 mmol), NaH₂PO₄(252 mg, 2.10 mmol) and NaClO₂ (189.92 mg, 2.10 mmol) in H₂O (2 mL) andCH₃CN (25 mL) was stirred at 20° C. for 16 h. The mixture was extractedwith EtOAc and purified via preparative HPLC to afford6-[[1-(2-cyanophenyl)-4-piperidyl]amino]-3,5-dimethyl-pyridine-2-carboxylicacid (340 mg, 970.29 umol, 92.41% yield) as product. ESI-MS (EI⁺, m/z):351.3 [M+H]⁺.

Step 5: tert-ButylN-[[2-[4-[6-[[1-(2-cyanophenyl)-4-piperidyl]amino]-3,5-dimethyl-pyridine-2-carbonyl]piperazin-1-yl]phenyl]-methyl-oxo-{6}-sulfanylidene]carbamate

A mixture of tert-butylN-[methyl-oxo-(2-piperazin-1-ylphenyl)-{6}-sulfanylidene]carbamate (100mg, 294.59 umol),6-[[1-(2-cyanophenyl)-4-piperidyl]amino]-3,5-dimethyl-pyridine-2-carboxylicacid (103.23 mg, 294.59 umol), EDCI (84.71 mg, 441.89 umol), HOBT (59.71mg, 441.89 umol) and DIPEA (114.22 mg, 883.78 umol, 154.35 uL) in DMF (5mL) was stirred at 20° C. for 16 h. The mixture was purified viapreparative HPLC to afford tert-butylN-[[2-[4-[6-[[1-(2-cyanophenyl)-4-piperidyl]amino]-3,5-dimethyl-pyridine-2-carbonyl]piperazin-1-yl]phenyl]-methyl-oxo-{6}-sulfanylidene]carbamate(90 mg, 133.96 umol, 45.47% yield) as product. ESI-MS (EI⁺, m/z): 672.3[M+H]⁺.

Step 6:2-(4-(3,5-Dimethyl-6-(4-(2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)pyridin-2-ylamino)piperidin-1-yl)benzonitrile

A mixture of tert-butylN-[[2-[4-[6-[[1-(2-cyanophenyl)-4-piperidyl]amino]-3,5-dimethyl-pyridine-2-carbonyl]piperazin-1-yl]phenyl]-methyl-oxo-{6}-sulfanylidene]carbamate(80 mg, 119.07 umol) in TFA (2 mL) and DCM (6 mL) was stirred at 0° C.for 6 h. The mixture was purified via preparative HPLC to afford2-(4-(3,5-dimethyl-6-(4-(2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)pyridin-2-ylamino)piperidin-1-yl)benzonitrileI-126 (30 mg, 52.47 umol, 44.07% yield) as product. The stereochemistrywas arbitrarily assigned. ESI-MS (EI⁺, m/z): 572.3 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.05 (dd, J=7.9, 1.5 Hz, 1H), 7.60-7.53 (m, 2H), 7.48 (dd,J=12.4, 5.0 Hz, 1H), 7.40-7.32 (m, 2H), 7.11 (s, 1H), 7.01 (dd, J=14.2,7.7 Hz, 2H), 4.24-4.12 (m, 1H), 3.98 (d, J=7.6 Hz, 1H), 3.56 (d, J=12.2Hz, 2H), 3.49 (s, 2H), 3.43 (s, 3H), 3.16 (s, 2H), 2.99 (dd, J=20.3, 8.5Hz, 5H), 2.23 (d, J=10.8 Hz, 2H), 2.19 (s, 3H), 2.07 (s, 3H), 1.72 (qd,J=11.8, 3.9 Hz, 2H).

Example 28:2-(4-(6-(1-(2-Cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpicolinoyl)piperazin-1-yl)benzenesulfonamide,I-66

Synthetic Scheme:

Procedures and Characterization:

The procedure was similar to that of example 27.

The analysis method was following Method B and the separation method wasfollowing Method D.

2-(4-(6-(1-(2-Cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpicolinoyl)piperazin-1-yl)benzenesulfonamide

ESI-MS (EI⁺, m/z): 574.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) 8.04 (dd,J=7.9, 1.5 Hz, 1H), 7.69-7.53 (m, 2H), 7.52-7.45 (m, 1H), 7.39 (d, J=8.0Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.08-6.94 (m, 2H), 5.56(s, 2H), 4.25-4.08 (m, 1H), 4.00 (d, J=7.7 Hz, 1H), 3.54 (t, J=13.6 Hz,4H), 3.18 (s, 2H), 2.99 (dd, J=19.5, 8.9 Hz, 3H), 2.23 (s, 2H), 2.19 (s,3H), 2.07 (s, 3H), 1.73 (qd, J=11.6, 3.7 Hz, 2H).

Example 29:(S)-2-(4-(6-(1-(2-Cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpicolinoyl)-3-methylpiperazin-1-yl)benzenesulfonamide,I-26

Synthetic Scheme:

Procedures and Characterization:

The procedure was same as the procedure of example 27.

The analysis method was following Method B and the separation method wasfollowing Method D.

(S)-2-(4-(6-(1-(2-Cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpicolinoyl)-3-methylpiperazin-1-yl)benzenesulfonamide

ESI-MS (EI⁺, m/z): 588.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.03 (dd,J=7.9, 1.3 Hz, 1H), 7.62-7.53 (m, 2H), 7.48 (dd, J=10.7, 4.9 Hz, 1H),7.41 (d, J=8.0 Hz, 1H), 7.33 (td, J=7.7, 2.6 Hz, 1H), 7.11 (d, J=13.1Hz, 1H), 7.06-6.96 (m, 2H), 5.63 (s, 2H), 5.23-4.70 (m, 1H), 4.26-4.09(m, 1H), 4.01 (t, J=7.5 Hz, 1H), 3.93 (s, 0.5H), 3.63-3.49 (m, 2.5H),3.46 (d, J=13.6 Hz, 0.5H), 3.30 (dt, J=11.6, 7.3 Hz, 2H), 3.16-3.07 (m,1H), 3.06-2.87 (m, 3H), 2.69 (td, J=11.4, 2.9 Hz, 0.5H), 2.25-2.13 (m,5H), 2.07 (d, J=6.1 Hz, 3H), 1.82-1.63 (m, 2H), 1.58-1.46 (m, 3H).

Example 30:2-(4-(6-(1-(2-Cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpicolinoyl)piperazin-1-yl)-6-fluorobenzenesulfonamide,I-16

Synthetic Scheme:

Procedures and Characterization:

The procedure was same as example the procedure of example 27.

The analysis method was following Method B and the separation method wasfollowing Method D.

2-(4-(6-(1-(2-Cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpicolinoyl)piperazin-1-yl)-6-fluorobenzenesulfonamide

ESI-MS (EI⁺, m/z): 592.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (dd,J=7.6, 1.5 Hz, 1H), 7.53-7.45 (m, 2H), 7.12 (d, J=7.8 Hz, 2H), 7.08-6.94(m, 3H), 5.85 (s, 2H), 4.22-4.07 (m, 1H), 4.00 (d, J=7.5 Hz, 1H), 3.56(m, 5H), 3.18 (s, 2H), 2.99 (t, J=11.4 Hz, 4H), 2.20 (m, 5H), 2.07 (s,3H), 1.79-1.66 (m, 2H).

Example 31:2-(4-(6-(1-(2-Cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpicolinoyl)piperazin-1-yl)pyridine-3-sulfonamide,I-25

Synthetic Scheme:

Procedures and Characterization:

The procedure was same as example the procedure of example 27.

The analysis method was following Method B and the separation method wasfollowing Method D.

2-(4-(6-(1-(2-Cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpicolinoyl)piperazin-1-yl)pyridine-3-sulfonamide

ESI-MS (EI⁺, m/z): 575.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.53 (d,J=3.8 Hz, 1H), 8.30 (d, J=7.5 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.48 (t,J=7.7 Hz, 1H), 7.25 (d, J=5.0 Hz, 1H), 7.10 (s, 1H), 7.04 (d, J=8.3 Hz,1H), 6.99 (t, J=7.5 Hz, 1H), 5.61 (s, 2H), 4.16 (d, J=6.7 Hz, 1H), 4.01(d, J=7.1 Hz, 3H), 3.56 (d, J=11.8 Hz, 2H), 3.51 (s, 2H), 3.35 (s, 2H),3.21 (s, 2H), 3.02 (t, J=11.3 Hz, 2H), 2.22 (d, J=11.3 Hz, 2H), 2.18 (s,3H), 2.07 (s, 3H), 1.74 (dd, J=22.1, 11.0 Hz, 2H).

Example 32:2-(4-(5-(1-(2-Cyanophenyl)azetidin-3-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide, 1-130

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: tert-Butyl N-[1-(2-cyanophenyl)azetidin-3-yl]carbamate

A mixture of 2-fluorobenzonitrile (1.50 g, 12.39 mmol), tert-butylN-(azetidin-3-yl)carbamate (2.35 g, 13.63 mmol) and K₂CO₃(3.44 g, 24.78mmol) in CH₃CN (50 mL) was stirred at 100° C. for 16 h. The mixture waspurified by SGC (EtOAc:PE=1:5) to afford tert-butyl N-[1-(2-cyanophenyl)azetidin-3-yl]carbamate (680 mg, 2.49 mmol, 20.08% yield) as product.ESI-MS (EI⁺, m/z): 274.1 [M+H]⁺.

Step 2: 2-(3-Aminoazetidin-1-yl)benzonitrile

A mixture of tert-butyl N-[1-(2-cyanophenyl)azetidin-3-yl]carbamate (700mg, 2.56 mmol) in TFA (5 mL) and DCM (5 mL) was stirred at 20° C. for 4h. The mixture was concentrated to afford2-(3-aminoazetidin-1-yl)benzonitrile (440 mg, 2.54 mmol, 99.23% yield)as product. ESI-MS (EI⁺, m/z): 174.1 [M+H]⁺.

Step 3:2-(4-(5-(1-(2-Cyanophenyl)azetidin-3-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

A mixture of 2-(3-aminoazetidin-1-yl)benzonitrile (100 mg, 577.33 umol),2-[4-(5-bromo-2,4-dimethyl-benzoyl)piperazin-1-yl]benzenesulfonamide(313.40 mg, 692.80 umol), tBuONa (83.14 mg, 866 umol), Pd₂(dba)₃ (5.29mg, 5.77 umol) and BINAP (10.78 mg, 17.32 umol) in toluene (5 mL) wasstirred at 80° C. for 17 h. The mixture was filtered and purified viapreparative HPLC to afford2-[4-[5-[[1-(2-cyanophenyl)azetidin-3-yl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamideI-130 (10 mg, 18.36 umol, 3.18% yield) as product. ESI-MS (EI⁺, m/z):545.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J=7.8 Hz, 1H), 7.61 (t,J=7.0 Hz, 1H), 7.45-7.32 (m, 4H), 6.96 (s, 1H), 6.74 (t, J=7.4 Hz, 1H),6.46 (d, J=8.1 Hz, 1H), 6.23 (s, 1H), 5.52 (s, 2H), 4.71 (s, 1H), 4.56(s, 1H), 4.38 (s, 1H), 4.06 (s, 1H), 3.92 (s, 1H), 3.87 (d, J=6.2 Hz,1H), 3.49 (s, 2H), 3.18 (s, 4H), 2.23 (s, 3H), 2.16 (s, 3H).

Example 33: 2-(4-(5-(3-(2-Cyanophenyl)-3-azabicyclo[3.1.0]hexan-6-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-132

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 2-(6-Amino-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile

A mixture of tert-butylN-[3-(2-cyanophenyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (400 mg,1.34 mmol) in TFA (10 mL) and DCM (10 mL) was stirred at 20° C. for 4 h.The mixture was concentrated to afford2-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile (250 mg, 1.25mmol, 93.63% yield) as product. ESI-MS (EI⁺, m/z): 200.1 [M+H]⁺.

Step 2: Methyl5-(3-(2-cyanophenyl)-3-azabicyclo[3.1.0]hexan-6-ylamino)-2,4-dimethylbenzoate

A mixture of 2-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile (20mg, 100.38 umol), methyl 5-bromo-2,4-dimethyl-benzoate (24.40 mg, 100.38umol), tBuONa (14.45 mg, 150.56 umol), Pd₂(dba)₃ (1.84 mg, 2.01 umol)and BrettPhos (2.16 mg, 4.02 umol) in toluene (5 mL) was stirred at 80°C. for 17 h. The mixture was filtered and purified by SGC to get methyl5-[[3-(2-cyanophenyl)-3-azabicyclo[3.1.0]hexan-6-yl]amino]-2,4-dimethyl-benzoate(5 mg, 13.83 umol, 13.78% yield) as product. ESI-MS (EI⁺, m/z): 362.2[M+H]⁺.

Step 3:5-[[3-(2-Cyanophenyl)-3-azabicyclo[3.1.0]hexan-6-yl]amino]-2,4-dimethyl-benzoicacid

A mixture of methyl5-[[3-(2-cyanophenyl)-3-azabicyclo[3.1.0]hexan-6-yl]amino]-2,4-dimethyl-benzoate(40 mg, 110.67 umol) and LiOH (21.20 mg, 885.36 umol) in MeOH (5 mL) andH₂O (499.95 uL) was stirred at 60° C. for 17 h. The mixture wasextracted with EtOAc after adjusting the pH to 4. The organic layerswere concentrated to afford5-[[3-(2-cyanophenyl)-3-azabicyclo[3.1.0]hexan-6-yl]amino]-2,4-dimethyl-benzoicacid (36 mg, 103.62 umol, 93.63% yield) as product. ESI-MS (EI⁺, m/z):348.3 [M+H]⁺.

Step 4: 2-(4-(5-(3-(2-Cyanophenyl)-3-azabicyclo[3.1.0]hexan-6-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-[4-[5-[[3-(2-cyanophenyl)-3-azabicyclo[3.1.0]hexan-6-yl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamide,I-132. ESI-MS (EI⁺, m/z): 571.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.02(d, J=7.8 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.8 Hz, 2H), 7.38(t, J=7.9 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 6.92 (s, 1H), 6.75 (t, J=7.5Hz, 1H), 6.71-6.64 (m, 2H), 5.55 (s, 2H), 4.13 (s, 2H), 3.96 (s, 1H),3.77-3.47 (m, 4H), 3.06 (m, 5H), 2.38 (s, 1H), 2.23 (s, 3H), 2.09 (s,3H), 1.91 (s, 2H).

Example 34:2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-4-methoxy-2-methylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-127

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 5-Bromo-4-methoxy-2-methyl-benzoic Acid

To a solution of 4-methoxy-2-methyl-benzoic acid (1 g, 6.02 mmol) and Fe(672.20 mg, 12.04 mmol) in chloroform (20 mL) was added bromine (1.06 g,6.62 mmol) at 5° C., and the mixture was stirred at rt for 16 h. Thenthe pH was adjusted to 3-4 and the mixture was extracted with EtOAc. Theorganic layers were concentrated to afford5-bromo-4-methoxy-2-methyl-benzoic acid (1 g, 4.08 mmol, 67.78% yield)as product. ESI-MS (EI⁺, m/z): 245 [M+H]⁺.

Step 2: Methyl 5-bromo-4-methoxy-2-methyl-benzoate

A mixture of 5-bromo-4-methoxy-2-methyl-benzoic acid (950 mg, 3.88 mmol)in HCl/MeOH (10 mL) was stirred at 70° C. for 16 h. The mixture wasconcentrated to afford methyl 5-bromo-4-methoxy-2-methyl-benzoate (1 g,3.86 mmol, 99.47% yield) as product. ESI-MS (EI⁺, m/z): 259 [M+H]⁺.

Step 3: Methyl5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-4-methoxy-2-methyl-benzoate

A mixture of 2-(4-amino-1-piperidyl)benzonitrile (1.10 g, 5.47 mmol),methyl 5-bromo-4-methoxy-2-methyl-benzoate (944.04 mg, 3.65 mmol),tBuONa (700.29 mg, 7.29 mmol), Pd₂(dba)₃ (66.75 mg, 72.93 umol) andBrettPhos (78.26 mg, 145.87 umol) in 1,4-dioxane (70 mL) was stirred at90° C. for 17 h. The mixture was purified by SGC (EtOAc:PE=1:10) toafford methyl5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-4-methoxy-2-methyl-benzoate(450 mg, 1.19 mmol, 32.52% yield) as product. ESI-MS (EI⁺, m/z): 380.2[M+H]⁺.

Step 4:5-[[1-(2-Cyanophenyl)-4-piperidyl]amino]-4-methoxy-2-methyl-benzoic Acid

A mixture of methyl5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-4-methoxy-2-methyl-benzoate(410 mg, 1.08 mmol) and LiOH (207.03 mg, 8.64 mmol) in MeOH (5 mL) andH₂O (0.5 mL) was stirred at 60° C. for 17 h. The mixture was extractedwith EtOAc after adjusting the pH value to 4. The organic layers wereconcentrated to afford5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-4-methoxy-2-methyl-benzoic acid(350 mg, 957.80 umol, 88.69% yield) as product. ESI-MS (EI⁺, m/z): 366.0[M+H]⁺.

Step 5:2-[4-[5-[[1-(2-Cyanophenyl)-4-piperidyl]amino]-4-methoxy-2-methyl-benzoyl]piperazin-1-yl]benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-[4-[5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-4-methoxy-2-methyl-benzoyl]piperazin-1—yl]benzenesulfonamide,I-127. ESI-MS (EI⁺, m/z): 589.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.04(dd, J=7.9, 1.5 Hz, 1H), 7.60 (td, J=7.9, 1.6 Hz, 1H), 7.56 (dd, J=7.7,1.5 Hz, 1H), 7.51-7.45 (m, 1H), 7.40-7.32 (m, 2H), 7.07-6.96 (m, 2H),6.60 (s, 1H), 6.48 (s, 1H), 5.53 (s, 2H), 4.16 (d, J=7.3 Hz, 1H), 3.85(s, 3H), 3.60 (s, 1H), 3.48 (d, J=32.2 Hz, 4H), 3.17 (s, 2H), 2.99 (s,3H), 2.23 (m, 5H), 1.73 (d, J=40.3 Hz, 2H).

Example 35:2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2-methoxy-4-methylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-105

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1:5-[[1-(2-Cyanophenyl)-4-piperidyl]amino]-2-methoxy-4-methyl-benzoi

A mixture of 2-(4-amino-1-piperidyl)benzonitrile (1.10 g, 5.47 mmol),methyl 5-bromo-2-methoxy-4-methyl-benzoate (944.84 mg, 3.65 mmol),Cs₂CO₃ (700.29 mg, 7.29 mmol), Pd₂(dba)₃ (66.75 mg, 72.93 umol) andBrettPhos (78.26 mg, 145.87 umol) in 1,4-dioxane (20 mL) was stirred at90° C. for 17 h. The mixture was purified by SGC (EtOAc:PE=1:10) toafford5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methoxy-4-methyl-benzoic acid(880 mg, 2.41 mmol, 66.04% yield) as product. ESI-MS (EI⁺, m/z): 366.0[M+H]⁺.

Step 2:2-[4-[5-[[1-(2-Cyanophenyl)-4-piperidyl]amino]-2-methoxy-4-methyl-benzoyl]piperazin-1-yl]benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-[4-[5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methoxy-4-methyl-benzoyl]piperazin-1-yl]benzenesulfonamide,I-105. ESI-MS (EI⁺, m/z): 589.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.03(dd, J=7.9, 1.5 Hz, 1H), 7.60 (td, J=7.9, 1.5 Hz, 1H), 7.57 (dd, J=7.7,1.5 Hz, 1H), 7.52-7.46 (m, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.35 (t, J=7.6Hz, 1H), 7.06-6.97 (m, 2H), 6.71 (s, 1H), 6.62 (s, 1H), 5.58 (s, 2H),3.79 (s, 3H), 3.65-3.41 (m, 5H), 3.16 (m, 3H), 2.97 (dd, J=23.1, 11.9Hz, 4H), 2.23 (t, 2H), 2.17 (s, 3H), 1.81-1.64 (m, 2H).

Example 36:2-(4-(5-(1-(2-Cyanophenyl)-3-methylpiperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-43

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: tert-Butyl 4-amino-3-methyl-piperidine-1-carboxylate

To a solution of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (5g, 23.44 mmol), ammonium formate (8.87 g, 140.67 mmol), molecular sieves(1 g) and NaCNBH₃ (1.77 g, 28.13 mmol) in MeOH (50 mL) was added NaCNBH₃(1.77 g, 28.13 mmol) at 20° C., after 16 h. The mixture was purified bySGC to afford tert-butyl 4-amino-3-methyl-piperidine-1-carboxylate (3.10g, 14.47 mmol, 61.71% yield) as product. ESI-MS (EI⁺, m/z): 159.3[M+H]⁺.

Step 2: 3-Methylpiperidin-4-amine

A mixture of tert-butyl 4-amino-3-methyl-piperidine-1-carboxylate (6.40g, 29.86 mmol) in HCl (4N in dioxane) (100 mL) was stirred at 20° C. for3 h. The mixture was concentrated to get 3-methylpiperidin-4-amine (3.10g, 27.15 mmol, 90.92% yield) as product. ESI-MS (EI⁺, m/z): 115.3[M+H]⁺.

Step 3: 2-(4-Amino-3-methyl-1-piperidyl)benzonitrile

A mixture of 2-fluorobenzonitrile (3.20 g, 26.42 mmol),3-methylpiperidin-4-amine (3.02 g, 26.42 mmol) and K₂CO₃ (11.02 g, 79.27mmol) in DMF (50 mL) was stirred at 120° C. for 16 h. The mixture waspurified by SGC to afford 2-(4-amino-3-methyl-1-piperidyl)benzonitrile(1.50 g, 6.97 mmol, 26.37% yield) as product. ESI-MS (EI⁺, m/z): 216.1[M+H]⁺.

Step 4: Methyl5-[[1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoate

A mixture of 2-(4-amino-3-methyl-1-piperidyl)benzonitrile (410 mg, 1.90mmol), methyl 5-bromo-2,4-dimethyl-benzoate (461.89 mg, 1.90 mmol),tBuONa (273.60 mg, 2.85 mmol), Pd₂(dba)₃ (34.81 mg, 38 umol) andBrettPhos (40.81 mg, 76 umol) in toluene (15 mL) was stirred at 80° C.for 17 h. The mixture was filtered and purified by SGC to afford methyl5-[[1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoate(220 mg, 582.81 umol, 30.67% yield) as product. ESI-MS (EI⁺, m/z): 378.3[M+H]⁺.

Step 5:5-[[1-(2-Cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoicAcid

A mixture of methyl5-[[1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoate(170 mg, 450.35 umol) and LiOH (86.29 mg, 3.60 mmol) in MeOH (20 mL) andH₂O (2 mL) was stirred at 60° C. for 17 h. The mixture was extractedwith EtOAc after adjusting the pH value to 4. The organic layers wereconcentrated to afford5-[[1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (150 mg, 412.71 umol, 91.64% yield) as product. ESI-MS (EI⁺, m/z):364.3 [M+H]⁺.

Step 6:2-[4-[5-[[1-(2-Cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamide

Following the amide coupling EDCI/HOBT method to afford2-[4-[5-[[1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamide,I-43. ESI-MS (EI⁺, m/z): 587.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.03(dd, J=7.9, 1.3 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H),7.49 (t, J=7.9 Hz, 1H), 7.40-7.31 (m, 2H), 7.08-6.97 (m, 2H), 6.92 (d,J=4.1 Hz, 1H), 6.46 (d, J=6.7 Hz, 1H), 5.54 (s, 2H), 3.59 (m, 4H), 3.05(m, 7H), 2.74-2.27 (m, 2H), 2.20 (s, 3H), 2.14 (d, J=10.7 Hz, 3H),2.07-1.89 (m, 2H), 1.17-1.03 (m, 3H).

Example 37:2-(4-(5-(1-(2-Chlorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzonitrile,I-37

Synthetic Scheme:

Procedures and Characterization:

The procedure was same as the procedure of example 5.

The analysis method was following Method B and the separation method wasfollowing Method D.

2-(4-(5-(1-(2-Chlorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzonitrile

ESI-MS (EI⁺, m/z): 528.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.59 (dd,J=7.6, 1.3 Hz, 1H), 7.53-7.48 (m, 1H), 7.36 (dd, J=7.9, 1.3 Hz, 1H),7.24-7.20 (m, 1H), 7.10-7.04 (m, 2H), 7.01 (d, J=8.3 Hz, 1H), 6.99-6.95(m, 1H), 6.92 (s, 1H), 6.49 (s, 1H), 4.04 (d, J=17.5 Hz, 2H), 3.52 (t,J=4.8 Hz, 2H), 3.39 (dd, J=44.5, 19.5 Hz, 4H), 3.31-3.22 (m, 2H), 3.10(s, 2H), 2.82 (dd, J=24.3, 12.3 Hz, 2H), 2.22 (m, 5H), 2.13 (s, 3H),1.69 (dd, J=45.7, 9.9 Hz, 2H).

Example 38:(5-(1-(2-Chlorophenyl)piperidin-4-ylamino)-2,4-dimethylphenyl)(4-(5-fluoropyridin-2-yl)piperazin-1-yl)methanone,I-36

Synthetic Scheme:

Procedures and Characterization:

The procedure was same as the procedure of example 5.

The analysis method was following Method B and the separation method wasfollowing Method D.

(5-(1-(2-Chlorophenyl)piperidin-4-ylamino)-2,4-dimethylphenyl)(4-(5-fluoropyridin-2-yl)piperazin-1-yl)methanone

ESI-MS (EI⁺, m/z): 522.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.06 (d,J=3.0 Hz, 1H), 7.36 (dd, J=7.9, 1.3 Hz, 1H), 7.29 (dd, J=8.5, 2.3 Hz,1H), 7.21 (dd, J=11.4, 3.9 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.97 (dd,J=10.8, 4.4 Hz, 1H), 6.93 (s, 1H), 6.63 (dd, J=9.2, 3.2 Hz, 1H), 6.49(s, 1H), 3.94 (d, J=4.1 Hz, 2H), 3.55 (t, J=5.1 Hz, 2H), 3.41 (s, 8H),2.81 (d, J=9.9 Hz, 2H), 2.29-2.16 (m, 5H), 2.14 (s, 3H), 1.69 (d, J=36.6Hz, 2H).

Example 39:3-(4-(5-(1-(2-Chlorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-4

Synthetic Scheme:

Procedures and Characterization:

The procedure was same as the procedure of example 5.

The analysis method was following Method B and the separation method wasfollowing Method D.

3-(4-(5-(1-(2-Chlorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

ESI-MS (EI⁺, m/z): 582.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.43 (s, 1H),7.40 (dd, J=3.7, 2.3 Hz, 2H), 7.36 (dd, J=7.9, 1.4 Hz, 1H), 7.23-7.19(m, 1H), 7.10-7.07 (m, 1H), 7.05 (dd, J=8.0, 1.3 Hz, 1H), 6.96 (td,J=7.8, 1.4 Hz, 1H), 6.92 (s, 1H), 6.49 (s, 1H), 4.86 (s, 2H), 3.97 (d,J=3.2 Hz, 2H), 3.41 (dd, J=32.9, 23.4 Hz, 8H), 3.14 (s, 2H), 2.81 (d,J=11.3 Hz, 2H), 2.22 (m, J=39.5 Hz, 5H), 2.14 (s, 3H), 1.68 (d, J=50.2Hz, 2H).

Example 40:N-(1-(2-Cyanophenyl)piperidin-4-yl)-5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzamide,I-97

Synthetic Scheme:

Procedures and Characterization:

The procedure was same as the procedure of example 5.

The analysis method was following Method B and the separation method wasfollowing Method D.

N-(1-(2-Cyanophenyl)piperidin-4-yl)-5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzamide

ESI-MS (EI⁺, m/z): 533.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.57 (dd,J=7.6, 1.4 Hz, 2H), 7.52-7.41 (m, 2H), 7.07-6.98 (m, 4H), 6.92 (s, 1H),6.69 (s, 1H), 5.67 (d, J=8.1 Hz, 1H), 4.24-4.11 (m, 1H), 3.63-3.49 (m,5H), 3.38 (d, J=8.2 Hz, 1H), 2.99 (q, J=10.6 Hz, 4H), 2.32 (d, J=6.5 Hz,3H), 2.24 (t, J=10.5 Hz, 4H), 2.13 (s, 3H), 1.85-1.68 (m, 4H).

Example 41:(R)-2-(4-(3,5-Dimethyl-6-(4-(2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)pyridin-2-ylamino)piperidin-1-yl)benzonitrile,I-110

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1:(R)-2-(4-(3,5-Dimethyl-6-(4-(2-(S-methylsulfonimidoyl)N-Boc-phenyl)piperazine-1-carbonyl)pyridin-2-ylamino)piperidin-1-yl)benzonitrile

To a solution of (R)-1-(2-(S-methylsulfonimidoyl)N-Boc-phenyl)piperazine(170 mg, 500.81 umol) and6-(1-(2-cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpicolinic acid(228.14 mg, 651.05 umol) in DMF (5 mL) was added EDCI (144.01 mg, 751.21umol), HOBT (101.50 mg, 751.21 umol) and DIPEA (194.17 mg, 1.50 mmol,262.39 uL). The reaction mixture was stirred at rt for 16 h, thendiluted with H₂O (200 mL) and extracted with EtOAc (60 mL×3), Thecombined organic layer was washed with brine, dried (Na₂SO₄), filteredand concentrated to afford(R)-2-(4-(3,5-dimethyl-6-(4-(2-(S-methylsulfonimidoyl)N-Boc-phenyl)piperazine-1-carbonyl)pyridin-2-ylamino)piperidin-1-yl)benzonitrile(300 mg, 0.446 mmol, 89% yield) as product. ESI-MS (EI⁺, m/z): 672.0[M+H]⁺.

Step 2:(R)-2-(4-(3,5-Dimethyl-6-(4-(2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)pyridin-2-ylamino)piperidin-1-yl)benzonitrile

To a solution of(R)-2-(4-(3,5-dimethyl-6-(4-(2-(S-methylsulfonimidoyl)N-Boc-phenyl)piperazine-1-carbonyl)pyridin-2-ylamino)piperidin-1-yl)benzonitrile(300 mg, 0.446 mmol) in DCM (6 mL) was added TFA (2 mL) at rt. Thereaction mixture was stirred at rt for 3 h, then concentrated andpurified via preparative HPLC to afford(R)-2-(4-(3,5-dimethyl-6-(4-(2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)pyridin-2-ylamino)piperidin-1-yl)benzonitrileI-110 (70 mg, 122.44 umol, 27.45% yield) as a white solid. ESI-MS (EI⁺,m/z): 572.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=7.9 Hz, 1H),7.57 (t, J=7.9 Hz, 2H), 7.49 (t, J=7.9 Hz, 1H), 7.36 (dd, J=15.1, 7.6Hz, 2H), 7.11 (s, 1H), 7.06-6.95 (m, 2H), 4.17 (s, 1H), 3.99 (d, J=7.6Hz, 1H), 3.60-3.41 (m, 7H), 3.16 (s, 2H), 3.00 (t, J=11.3 Hz, 4H), 2.22(d, J=18.7 Hz, 5H), 2.07 (s, 3H), 1.72 (dd, J=19.7, 10.8 Hz, 4H).

Example 42:(R)-2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-methylpiperazin-1-yl)pyridine-3-sulfonamide,I-122

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: (R)-tert-Butyl3-methyl-4-(3-sulfamoylpyridin-2-yl)piperazine-1-carboxylate

To a solution of 2-chloropyridine-3-sulfonamide (600 mg, 3.115 mmol) and(R)-tert-butyl 3-methylpiperazine-1-carboxylate (1.871 g, 9.34 mmol) inDMF (10 mL) was added K₂CO₃ (1.293 g, 9.36 mmol) at rt. The reactionmixture was stirred at 130° C. under microwave for 4 h, then cooled tort and purified via preparative HPLC to afford (R)-tert-butyl3-methyl-4-(3-sulfamoylpyridin-2-yl)piperazine-1-carboxylate (600 mg,1.68 mmol, 54% yield) as product. ESI-MS (EI⁺, m/z): 357.0 [M+H]⁺.

Step 2: (R)-2-(2-Methylpiperazin-1-yl)pyridine-3-sulfonamide

A mixture of tert-butyl (R)-tert-butyl3-methyl-4-(3-sulfamoylpyridin-2-yl)piperazine-1-carboxylate (120 mg,336.66 umol) in DCM (9 mL) and TFA (3 mL) was stirred at rt for 3 h,then concentrated to afford2-[(2R)-2-methylpiperazin-1-yl]pyridine-3-sulfonamide (120 mg, 468.16umol) as product. ESI-MS (EI⁺, m/z): 257.0 [M+H]⁺.

Step 3:(R)-2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-methylpiperazin-1-yl)pyridine-3-sulfonamide

Followed the amide coupling EDCI/HOBT method to afford(R)-2-(4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-methylpiperazin-1-yl)pyridine-3-sulfonamideI-122 as product. ESI-MS (EI⁺, m/z): 588.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.44 (s, 1H), 8.22 (d, J=7.7 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H),7.59 (t, J=7.5 Hz, 1H), 7.42 (s, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.07 (t,J=7.5 Hz, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.40 (t, J=28.6 Hz, 1H),4.90-4.27 (m, 2H), 3.97-3.44 (m, 6H), 3.29-2.73 (m, 5H), 2.24-1.89 (m,8H), 1.82-1.57 (m, 2H), 1.35-1.15 (m, 3H).

Example 43:(R)-2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-methylpiperazin-1-yl)-N-methylnicotinamide,I-123

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 2-Chloro-N-methylnicotinamide

To a solution of 2-chloropyridine-3-carboxylic acid (4 g, 25.39 mmol) inDCM (80 mL) was added DMF (92.79 mg, 1.27 mmol) and then oxalyldichloride (6.45 g, 50.78 mmol). The reaction mixture was stirred at rtfor 2 h, then concentrated to dryness, the residue was dissolved in1,4-dioxane (80 mL) and added this solution to methanamine (7.89 g,253.90 mmol) and stirred at rt for 3 h. Then the mixture was dilutedwith H₂O (200 mL) and extracted with EtOAc (100 mL×3). The combinedorganic layer was washed with brine, dried (Na₂SO₄), filtered,concentrated and purified by chromatography (silica, ethylacetate/petroleum ether=1/3) to afford2-chloro-N-methyl-pyridine-3-carboxamide (3.80 g, 22.27 mmol, 87.71%yield) as product. ESI-MS (EI⁺, m/z): 171.6 [M+H]⁺.

Step 2: (R)-tert-Butyl3-methyl-4-(3-(methylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate

At rt, to a solution of 2-chloro-N-methyl-pyridine-3-carboxamide (300mg, 1.76 mmol) in DMF (8 mL) was added (R)-tert-butyl3-methylpiperazine-1-carboxylate (1.06 g, 5.28 mmol) and K₂CO₃ (729.75mg, 5.28 mmol). The reaction mixture was stirred at 130° C. for 4 hunder microwave. Then cooled to rt and diluted with H₂O (100 mL),extracted with EtOAc (60 mL×3), the combined organic layer was washedwith brine, dried (Na₂SO₄), filtered, concentrated and purified bychromatography (silica, ethyl acetate/petroleum ether=1/5) to afford(R)-tert-butyl3-methyl-4-(3-(methylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate(450 mg, 1.35 mmol, 76.70% yield) as solid. ESI-MS (EI⁺, m/z): 335.0[M+H]⁺.

Step 3: (R)-2-(2-Methylpiperazin-1-yl)pyridine-3-sulfonamide

A mixture of (R)-tert-butyl3-methyl-4-(3-(methylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate(250 mg, 747.59 umol) in 4 N HCl/1,4-dioxane (10 mL) was stirred at rtfor 2h, then concentrated to afford(R)-N-methyl-2-(2-methylpiperazin-1-yl)nicotinamide (182 mg, 0.67 mmol,90% yield) as product. ESI-MS (EI⁺, m/z): 235.3 [M+H]⁺.

Step 4:(R)-2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-methylpiperazin-1-yl)-N-methylnicotinamide

Followed the amide coupling EDCI/HOBT method to afford(R)-2-(4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-methylpiperazin-1-yl)-N-methylnicotinamide1-123 (200 mg, 353.54 umol, 54.50% yield) as a white solid. ESI-MS (EI⁺,m/z): 566.0 [M+H. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=4.6 Hz, 1H),8.22 (d, J=2.7 Hz, 1H), 7.75-7.50 (m, 3H), 7.18 (d, J=8.3 Hz, 1H), 7.07(t, J=7.5 Hz, 1H), 6.87 (s, 2H), 6.42 (s, 1H), 4.87-4.26 (m, 2H),3.88-3.47 (m, 5H), 3.13 (s, 2H), 2.97 (t, J=10.5 Hz, 3H), 2.74 (d, J=4.3Hz, 3H), 2.12-2.00 (m, 8H), 1.69 (s, 2H), 1.32-1.05 (m, 4H).

Example 44:2-(4-(5-((1-(2-Cyanophenyl)piperidin-4-yl)(2-hydroxyethyl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-1

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: Methyl 5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate

At 0° C., to MeOH (80 mL) was added dropwise SOCl₂ (3.40 g, 28.60 mmol).After addition, the mixture was stirred at 0° C. for 20 min, then5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoic acid (2.50g, 7.15 mmol) was added to this mixture. The reaction mixture wasstirred at 60° C. for 4 h, then cooled to rt and concentrated. Theresidue was dissolved in EtOAc (200 mL) and washed with aqueousNaHCO₃(100 mL) and brine. The organic layer was washed with brine, driedover Na₂SO₄, filtered, concentrated and purified by chromatography(silica, ethyl acetate/petroleum ether=1/5) to afford methyl5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate (2.30 g,6.33 mmol, 88.51% yield) as a yellow solid. ESI-MS (EI⁺, m/z): 364.2[M+H]⁺.

Step 2: Methyl5-((1-(2-cyanophenyl)piperidin-4-yl)(2-hydroxyethyl)amino)-2,4-dimethylbenzoate

To a solution of methyl5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate (1 g,2.75 mmol) in DMF (20 mL) was added 2-iodoethanol (23.64 g, 137.50 mmol)and Cs₂CO₃ (2.69 g, 8.25 mmol). The reaction mixture was stirred at 90°C. for 48 h. Then the mixture was cooled to rt and purified viapreparative HPLC to afford methyl5-[[1-(2-cyanophenyl)-4-piperidyl]-(2-hydroxyethyl)amino]-2,4-dimethyl-benzoate(100 mg, 245.40 umol, 8.92% yield) as product. ESI-MS (EI⁺, m/z): 408.5[M+H]⁺.

Step 3:5-((1-(2-Cyanophenyl)piperidin-4-yl)(2-hydroxyethyl)amino)-2,4-dimethylbenzoicAcid

To a solution of methyl5-((1-(2-cyanophenyl)piperidin-4-yl)(2-hydroxyethyl)amino)-2,4-dimethylbenzoate(100 mg, 245.4 umol) in MeOH (8 mL) and H₂O (799.91 uL) was added LiOH(37.61 mg, 1.57 mmol). The reaction mixture was stirred at 60° C. for 16h, cooled to rt, diluted with H₂O (100 mL) and the pH adjusted to 4 to 5with 2 N HCl and then extracted with EtOAc (60 mL×3). The combinedorganic layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated to afford5-((1-(2-cyanophenyl)piperidin-4-yl)(2-hydroxyethyl)amino)-2,4-dimethylbenzoicacid (90 mg, 0.228 mmol, 93% yield) as product. ESI-MS (EI⁺, m/z): 394.0[M+H]⁺.

Step 4:2-(4-(5-((1-(2-Cyanophenyl)piperidin-4-yl)(2-hydroxyethyl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-(4-(5-((1-(2-cyanophenyl)piperidin-4-yl)(2-hydroxyethyl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamideI-1 as a white solid. ESI-MS (EI⁺, m/z): 617.2 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d6) δ 7.87 (d, J=7.5 Hz, 1H), 7.70-7.60 (m, 2H), 7.59-7.52 (m, 2H),7.35 (t, J=7.4 Hz, 1H), 7.12 (d, J=4.8 Hz, 2H), 7.09-7.01 (m, 2H), 6.97(s, 2H), 4.35 (dd, J=22.1, 16.9 Hz, 1H), 3.87 (s, 2H), 3.49 (d, J=11.5Hz, 2H), 3.27 (d, J=5.6 Hz, 4H), 3.15-2.74 (m, 9H), 2.23 (d, J=27.5 Hz,6H), 1.86 (d, J=11.2 Hz, 2H), 1.74-1.58 (m, 2H).

Example 45:2-(4-(5-((1-(2-Cyanophenyl)-3-methylpiperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-10

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: Ethyl5-((1-(2-cyanophenyl)-3-methylpiperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoate

To a solution of5-[[1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (102 mg, 487.74 umol) in DMF (15 mL) was added iodomethane (2.19 g,3.736 mmol) and Cs₂CO₃ (274.31 mg, 467.94 umol). The reaction mixturewas stirred at 90° C. for 16 h, then cooled to rt and diluted with H₂O(200 mL) and extracted with EtOAc (60 mL×3). The combined organic layerwas washed with brine, dried over Na₂SO₄, filtered, concentrated andpurified by chromatography (silica, ethyl acetate/petroleum ether=1/10)to afford ethyl5-((1-(2-cyanophenyl)-3-methylpiperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoate(137 mg, 0.326 mmol, 68.2% yield) as product. ESI-MS (EI⁺, m/z): 420.2[M+H]⁺.

Step 2:5-((1-(2-Cyanophenyl)-3-methylpiperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoicAcid

To a solution of ethyl5-((1-(2-cyanophenyl)-3-methylpiperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoate(137 mg, 0.326 mmol) in MeOH (12 mL) and H₂O (1.50 mL) was added LiOH(109 mg, 2.61 mmol). The reaction mixture was stirred at 60° C. for 16h, then cooled to rt and diluted with H₂O (100 mL), the pH was adjustedto 4 to 5 with 2 N HCl, then the mixture was extracted with EtOAc (60mL×3). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to afford5-((1-(2-cyanophenyl)-3-methylpiperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoicacid (120 mg, 0.306 mmol, 94% yield) as product. ESI-MS (EI⁺, m/z):392.2 [M+H]⁺.

Step 3:2-(4-(5-((1-(2-Cyanophenyl)-3-methylpiperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-(4-(5-((1-(2-cyanophenyl)-3-methylpiperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide1-10 as a white solid. ESI-MS (EI⁺, m/z): 615.8 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 7.87 (d, J=7.0 Hz, 1H), 7.69-7.44 (m, 4H), 7.35 (t, J=7.4 Hz,1H), 7.19-6.83 (m, 6H), 4.14-3.70 (m, 2H), 3.19 (s, 3H), 3.11-2.55 (m,8H), 2.24 (dd, J=30.0, 7.0 Hz, 7H), 2.01-1.23 (m, 3H), 1.09 (d, J=6.5Hz, 3H), 0.94-0.75 (m, 3H).

Example 46:2-(4-(5-(Allyl(1-(2-cyanophenyl)piperidin-4-yl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-46

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the product was obtainedby purified by SGC.

Step 1: Methyl5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate

At 0° C., to MeOH (80 mL) was added dropwise SOCl₂ (3.40 g, 28.60 mmol,2.07 mL). The mixture was stirred at 0° C. for 20 min, then5-(1-(2-cyanophenyl) piperidin-4-ylamino)-2,4-dimethylbenzoic acid (2.50g, 7.15 mmol) was added. The reaction mixture was stirred at 60° C. for4 h, then cooled to rt and concentrated. The residue was dissolved inEtOAc (150 mL) and washed with aqueous NaHCO₃(200 mL), brine (200 mL).The organic layer was washed with brine, dried over Na₂SO₄, filtered,concentrated and purified by chromatography (silica, ethylacetate/petroleum ether=1/5) to afford methyl5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate (2.30 g,6.33 mmol, 88.51% yield) as a yellow solid. ESI-MS (EI⁺, m/z): 364.2[M+H]⁺.

Step 2: Methyl 5-(allyl (1-(2-cyanophenyl) piperidin-4-yl)amino)-2,4-dimethylbenzoate

A mixture of methyl5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate (1.50 g,4.13 mmol), 3-bromoprop-1-ene (9.99 g, 82.60 mmol) and cesium carbonate(1.35 g, 4.13 mmol) in N,N-dimethylacetamide (30 mL) was stirred at 80°C. for 16 h, then the mixture was cooled to rt and diluted with H₂O (200mL) and extracted with EtOAc (80 mL×3). The combined organic layer waswashed with brine, dried over Na₂SO₄, filtered, concentrated andpurified by chromatography (silica, ethyl acetate/petroleum ether=1/20)to afford methyl 5-(allyl (1-(2-cyanophenyl) piperidin-4-yl)amino)-2,4-dimethylbenzoate (1.10 g, 2.73 mmol, 66.10% yield) as asolid. ESI-MS (EI⁺, m/z): 404.2 [M+H]⁺.

Step 3:5-(Allyl(1-(2-cyanophenyl)piperidin-4-yl)amino)-2,4-dimethylbenzoic Acid

To a solution of methyl5-(allyl(1-(2-cyanophenyl)piperidin-4-yl)amino)-2,4-dimethylbenzoate (1g, 2.48 mmol) in MeOH (100 mL) and H₂O (10 mL) was added LiOH (59.39 mg,2.48 mmol). The reaction mixture was stirred at 60° C. for 16 h, thencooled to rt and diluted with H₂O. The pH was adjusted to 3-4 with 2 NHCl aqueous solution. The mixture was extracted with EtOAc (80 mL×3),washed with brine, dried over Na₂SO₄, filtered and concentrated toafford5-(allyl(1-(2-cyanophenyl)piperidin-4-yl)amino)-2,4-dimethylbenzoic acid(900 mg, 2.31 mmol, 93% yield) as product. ESI-MS (EI⁺, m/z): 390.2[M+H]⁺.

Step 4:2-(4-(5-(Allyl(1-(2-cyanophenyl)piperidin-4-yl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-(4-(5-(allyl(1-(2-cyanophenyl)piperidin-4-yl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamideI-46 as a white solid. ESI-MS (EI⁺, m/z): 613.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.91-7.83 (m, 1H), 7.69-7.59 (m, 2H), 7.59-7.53 (m, 2H), 7.35(t, J=7.4 Hz, 1H), 7.16-7.08 (m, 2H), 7.05 (t, J=7.5 Hz, 1H), 6.98 (d,J=9.0 Hz, 3H), 5.66 (dq, J=10.5, 6.0 Hz, 1H), 5.04 (d, J=16.9 Hz, 1H),4.92 (d, J=10.5 Hz, 1H), 4.06-3.60 (m, 4H), 3.49 (d, J=10.2 Hz, 2H),3.33 (s, 2H), 2.92 (d, J=50.2 Hz, 4H), 2.79 (s, 3H), 2.27 (s, 3H), 2.18(s, 3H), 1.86 (s, 2H), 1.70 (s, 2H).

Example 47:2-(4-(5-((1-(2-Cyanophenyl)piperidin-4-yl)(propyl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-23

Synthetic Scheme:

Procedures and Characterization:

The procedure was similar to that of example 46.

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1:2-(4-(5-((1-(2-Cyanophenyl)piperidin-4-yl)(propyl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

To a solution of2-(4-(5-(allyl(1-(2-cyanophenyl)piperidin-4-yl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide(210 mg, 342.70 umol) in methanol (15 mL) was added Pd/C (199.80 mg,1.64 mmol). The mixture was hydrogenated for 16 h, then filtered,concentrated and the residue was purified via preparative HPLC to afford2-(4-(5-((1-(2-cyanophenyl)piperidin-4-yl)(propyl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamideI-23 (63 mg, 102.47 umol, 29.90% yield) as product. ESI-MS (EI⁺, m/z):615.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=7.8 Hz, 1H), 7.59(ddd, J=21.3, 16.7, 7.5 Hz, 4H), 7.35 (t, J=7.4 Hz, 1H), 7.11 (d, J=8.3Hz, 2H), 7.08-6.92 (m, 4H), 3.87 (s, 2H), 3.50 (d, J=11.2 Hz, 2H), 3.38(s, 2H), 3.09-2.72 (m, 9H), 2.23 (d, J=33.1 Hz, 6H), 1.82 (s, 2H), 1.73(s, 2H), 1.22 (dd, J=14.1, 6.9 Hz, 2H), 0.78 (t, J=7.3 Hz, 3H).

Example 48:2-(4-(5-((1-(2-Cyanophenyl)piperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide, I-51

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the crude was purified bySGC to obtain the target.

Step 1: 2-(4-Aminopiperidin-1-yl)benzonitrile

To a solution of 2-fluorobenzonitrile (10 g, 82.57 mmol),piperidin-4-amine (10.75 g, 107.34 mmol) in DMF (100 mL) was added K₂CO₃(28.49 g, 206.43 mmol). The reaction mixture was stirred at 85° C. for16 h. then cooled to r.t and diluted with H₂O (400 mL) and extractedwith EtOAc (100 mL×3). The combined organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated to afford the crudeproduct, which was purified by chromatography (silica,dichloromethane/methanol:1/10) to afford2-(4-amino-1-piperidyl)benzonitrile (9.60 g, 47.70 mmol, 57.77% yield)as product. ESI-MS (EI⁺, m/z): 202.0 [M+H]⁺.

Step 2: 5-(1-(2-Cyanophenyl) piperidin-4-ylamino)-2,4-dimethylbenzoicAcid

To a solution of methyl 5-bromo-2,4-dimethyl-benzoate (920 mg, 3.78mmol), 2-(4-amino-1-piperidyl)benzonitrile (989.04 mg, 4.91 mmol) intoluene (20 mL) was added BrettPhos (284.05 mg, 529.20 umol), Pd₂(dba)₃(242.30 mg, 264.60 umol) and sodium tert-butoxide (1.09 g, 11.34 mmol)under nitrogen. The reaction mixture was stirred at 80° C. for 16 h.then cooled to rt and diluted with H₂O (100 mL). The pH was adjusted to4 to 5 with 1 N HCl and then extracted with EtOAc (80 mL×3). Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to obtain the crude product, which waspurified by chromatography (silica, ethyl acetate/petroleum ether=1/3)to afford the desired product5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoic acid (1.10g, 3.15 mmol, 83.33% yield) as a solid. ESI-MS (EI⁺, m/z): 350.2 [M+H]⁺.

Step 3: Ethyl5-((1-(2-cyanophenyl)piperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoate

At rt, to a solution of5-[[1-(2-cyanophenyl)-4-piperidyl]amino]=2,4-dimethyl-benzoic acid (400mg, 1.14 mmol) in N,N-dimethylacetamide (30 mL) was added sodiumtert-butoxide (328.66 mg, 3.42 mmol) and iodoethane (3.56 g, 22.80mmol). Then reaction mixture was stirred at 80° C. for 16 h, cooled tort and diluted with H₂O (200 mL) and extracted with EtOAc (80 mL×3). Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered, concentrated and purified by chromatography (silica, ethylacetate/petroleum ether=1/10) to afford ethyl5-((1-(2-cyanophenyl)piperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoate(370 mg, 912.39 umol, 80.03% yield) as product. ESI-MS (EI⁺, m/z): 406.2[M+H]⁺.

Step 4:5-((1-(2-Cyanophenyl)piperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoicAcid

At rt, a solution of ethyl5-[[1-(2-cyanophenyl)-4-piperidyl]-ethyl-amino]-2,4-dimethyl-benzoate(300 mg, 739.77 umol) in MeOH (30 mL) and H₂O (3 mL) was added LiOH(141.74 mg, 5.92 mmol). The reaction mixture was stirred at 60° C. for16 h, cooled to rt and diluted with H₂O (200 mL). The pH was adjusted to3 to 4 with 1 N HCl and extracted with EtOAc (80 mL×3). The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford5-((1-(2-cyanophenyl)piperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoicacid (251 mg, 0.665 mmol, 90% yield) as product. ESI-MS (EI⁺, m/z):378.2 [M+H]⁺.

Step 5:2-(4-(5-((1-(2-Cyanophenyl)piperidin-4-yl)(ethyl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-[4-[5-[[1-(2-cyanophenyl)-4-piperidyl]-ethyl-amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamideI-51 as a white solid. ESI-MS (EI⁺, m/z): 601.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.87 (d, J=7.3 Hz, 1H), 7.72-7.48 (m, 4H), 7.35 (t, J=7.5 Hz,1H), 7.12 (d, J=11.0 Hz, 2H), 7.08-6.90 (m, 4H), 3.87 (s, 2H), 3.48 (d,J=10.9 Hz, 2H), 3.36 (d, J=10.5 Hz, 2H), 3.17-2.68 (m, 9H), 2.23 (d,J=28.6 Hz, 6H), 1.84 (d, J=11.0 Hz, 2H), 1.67 (d, J=10.1 Hz, 2H), 0.82(t, J=6.8 Hz, 3H).

Example 49:(R)-2-(4-(2,4-Dimethyl-5-(3-methyl-4-phenylpiperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile,I-47

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: (R)-2-Methyl-1-phenylpiperazine Hydrochloride

A mixture of tert-butyl (R)-tert-butyl3-methyl-4-phenylpiperazine-1-carboxylate (300 mg, 1.09 mmol) in 4 N HCl(1,4-dioxane, 10 mL) was stirred at rt for 3 h and concentrated toafford (R)-2-methyl-1-phenylpiperazine hydrochloride (208 mg, 0.977mmol, 90% yield) as product. ESI-MS (EI⁺, m/z): 177.2 [M+H]⁺.

Step 2:(R)-2-(4-(2,4-Dimethyl-5-(3-methyl-4-phenylpiperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile

Followed the amide coupling EDCI/HOBT method to afford(R)-2-(4-(2,4-dimethyl-5-(3-methyl-4-phenylpiperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrileI-47 as a white solid. ESI-MS (EI⁺, m/z): 508.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.68 (d, J=7.2 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.26-7.13 (m,3H), 7.06 (t, J=7.4 Hz, 1H), 6.90 (t, J=6.7 Hz, 3H), 6.77 (s, 1H), 6.43(d, J=5.9 Hz, 1H), 4.64-3.85 (m, 3H), 3.58-3.40 (m, 4H), 3.30-2.71 (m,6H), 2.15-1.96 (m, 8H), 1.71 (d, J=10.0 Hz, 2H), 0.89 (dd, J=73.1, 26.1Hz, 3H).

Example 50:(S)-2-(4-(2,4-Dimethyl-5-(3-methyl-4-phenylpiperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile,I-33

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: (S)-2-Methyl-1-phenylpiperazine Hydrochloride

A solution of (S)-tert-butyl 3-methyl-4-phenylpiperazine-1-carboxylate(300 mg, 1.09 mmol) in 4N HCl (in dioxane, 20 mL) was stirred for 3 h,then concentrated to obtain (S)-2-methyl-1-phenylpiperazinehydrochloride (210 mg, 0.986 mmol, 91% yield) as product. ESI-MS (EI⁺,m/z): 177.2 [M+H]⁺.

Step 2:(S)-2-(4-(2,4-Dimethyl-5-(3-methyl-4-phenylpiperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrile

Followed the amide coupling EDCI/HOBT method to afford(S)-2-(4-(2,4-dimethyl-5-(3-methyl-4-phenylpiperazine-1-carbonyl)phenylamino)piperidin-1-yl)benzonitrileI-33 as a white solid. ESI-MS (EI⁺, m/z): 508.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO) δ 7.63 (dd, J=43.8, 7.2 Hz, 2H), 7.37-7.12 (m, 3H), 7.06 (t, J=7.5Hz, 1H), 6.90 (s, 3H), 6.78 (d, J=6.8 Hz, 1H), 6.43 (s, 1H), 4.59-3.89(m, 3H), 3.44 (dd, J=32.8, 17.3 Hz, 5H), 3.24-2.79 (m, 5H), 2.25-1.86(m, 8H), 1.71 (s, 2H), 0.90 (dd, J=57.1, 19.8 Hz, 3H).

Example 51:2-(4-(5-(1-(3-Cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzonitriletrifluoroacetate, I-18

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method A and the separation method wasfollowing Method C.

Step 1: Methyl5-(1-(3-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate

The procedure for methyl5-(1-(3-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate was thesame as example 32. ESI-MS (EI⁺, m/z): 364.1 [M+H]⁺.

Step 2: 5-(1-(3-Cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoicAcid

To a solution of methyl5-(1-(3-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate (110 mg,crude) in MeOH (20 mL) and water (10 mL) was added LiOH (27 mg, 1.13mmol). The mixture was stirred at 60° C. for 3 h. Then the solvent wasremove and the residue was dissolved in water, the resulting mixture wasadjusted to pH 3 with 1M HCl, extracted with EtOAc (100 mL×2), then theorganic phase was washed with brine (50 mL), dried and concentrated togive 5-(1-(3-cyanophenyl) piperidin-4-ylamino)-2,4-dimethylbenzoic acid(120 mg, crude) as a yellow oil. ESI-MS (EI+, m/z): 350.2 [M+H]⁺.

Step 3:2-(4-(5-(1-(3-Cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzonitriletrifluoroacetate

Using EDCI/HOBT Generic Method B2-(4-(5-(1-(3-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzonitriletrifluoroacetate 1-18 was obtained. ESI-MS (EI⁺, m/z): 519.0 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD-d₄) δ: 7.59-7.68 (m, 2H), 7.38-7.42 (m, 1H),7.30-7.32 (m, 2H), 7.13-7.23 (m, 4H), 6.93 (s, 1H), 3.87-4.04 (m, 4H),3.63-3.67 (m, 1H), 3.51-3.53 (t, J=4.8 Hz, 2H), 3.14-3.24 (m, 4H),2.92-2.98 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H), 2.15 (d, J=11.6 Hz, 2H),1.77 (s, 2H).

Example 52:2-(4-(5-(1-(3-Chlorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzonitrile,I-17

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

The procedure for2-(4-(5-(1-(3-chlorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzonitrilewas similar to example 51. ESI-MS (EI+, m/z): 527.9 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ: 7.49-7.59 (m, 2H), 7.13-7.17 (t, J=8.0 Hz, 1H), 7.00-7.08(m, 2H), 6.90 (d, J=8.0 Hz, 2H), 6.78-6.82 (m, 2H), 6.47 (s, 1H),4.01-4.05 (m, 2H), 3.60-3.67 (t, J=14.0 Hz, 2H), 3.22-3.51 (m, 6H), 3.10(s, 2H), 2.89-2.98 (m, 2H), 2.19 (s, 3H), 2.11 (s, 3H), 1.50-1.74 (m,3H).

Example 53:2-(4-(5-(4-(2-Cyanophenyl)piperazine-1-carbonyl)-2,6-dimethylpyridin-3-ylamino)piperidin-1-yl)benzonitrile,I-13

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

The procedure for2-(4-(5-(4-(2-cyanophenyl)piperazine-1-carbonyl)-2,6-dimethylpyridin-3-ylamino)piperidin-1-yl)benzonitrilewas similar to example 51. ESI-MS (EI⁺, m/z): 520.0 [M+H]⁺. ¹H NMR (500MHz, CD₃OD-d₄) δ: 7.65-7.66 (m, 1H), 7.55-7.62 (m, 3H), 7.19-7.22 (t,J=8.0 Hz, 2H), 7.13-7.16 (t, J=7.5 Hz, 1H), 7.06-7.09 (t, J=8.0 Hz, 1H),6.98 (s, 1H), 3.98-4.05 (m, 2H), 3.53-3.60 (m, 6H), 3.15-3.24 (m, 3H),3.01-3.05 (t, J=11.5 Hz, 2H), 2.42 (s, 3H), 2.38 (s, 3H), 2.18 (d,J=10.5 Hz, 2H), 1.31-1.33 (m, 2H).

Example 54:2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,6-dimethylnicotinoyl)piperazin-1-yl)benzenesulfonamide,I-12

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

The procedure for2-(4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,6-dimethylnicotinoyl)piperazin-1-yl)benzenesulfonamidewas similar to example 51.

ESI-MS (EI+, m/z): 573.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ: 8.02-8.04(dd, J₁=7.5 Hz, J₂=1.0 Hz, 1H), 7.56-7.62 (m, 2H), 7.47-7.51 (m, 1H),7.34-7.39 (m, 2H), 7.00-7.05 (m, 2H), 6.73 (s, 1H), 5.52 (s, 2H),3.45-3.61 (m, 6H), 2.99-3.18 (m, 6H), 2.42 (s, 3H), 2.39 (s, 3H), 2.22(d, J=7.5 Hz, 2H), 1.72-1.80 (m, 2H).

Example 55: (S)-tert-butyl4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate,I-9

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: (S)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate

To a solution of (S)-4-benzyl 1-tert-butyl2-(hydroxymethyl)piperazine-1,4-dicarboxylate (1.5 g, 4.28 mmol) in MeOH(20 mL) was added 10% Pd/C (150 mg). The mixture was stirred at rt for 3h under H₂. Then the solid was remove by filtration and the filter wasconcentrated to give (S)-tert-butyl2-(hydroxymethyl)piperazine-1-carboxylate (850 mg, 3.93 mmol, 91.82%) asa white solid. ESI-MS (EI⁺, m/z): 217.3 [M+H]⁺.

Step 2: (S)-tert-butyl4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate

The procedure for (S)-tert-butyl4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylatewas HATU generic method A. ESI-MS (EI+, m/z): 548.0 [M+H]⁺. ¹H NMR (500MHz, CD₃OD-d₄) δ: 7.55-7.62 (m, 2H), 7.20 (d, J=8.5 Hz, 1H), 7.06-7.09(t, J=7.5 Hz, 1H), 6.96 (s, 1H), 6.49-6.58 (m, 2H), 3.47-4.32 (m, 9H),2.97-3.21 (m, 5H), 2.10-2.22 (m, 8H), 1.77 (d, J=10.0 Hz, 2H), 1.48 (s,9H).

Example 56:(S)-2-(4-(5-(3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-8

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

To a solution of (S)-tert-butyl4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate(170 mg, 0.31 mmol) in MeOH (2 mL) was added HCl (4M in dioxane, 4 mL).The mixture was stirred at rt for 2 h. Then the mixture was concentratedand the residue was dissolved in water, then saturated NaHCO₃ was addedto above mixture until the pH of the mixture was 8. The reaction mixturewas extracted with EtOAc (100 mL), and washed with water (50 mL) andbrine (50 mL). The resulting organic phase was dried, filtered andconcentrated. The residue was purified via preparative HPLC to give(S)-2-(4-(5-(3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrileI-8 (140 mg, 0.29 mmol, 93.19%) as a white solid.

ESI-MS (EI+, m/z): 448.3 [M+H]⁺. ¹H-NMR (500 MHz, MeOD) δ: 7.55-7.62 (m,2H), 7.20 (d, J=8.5 Hz, 1H), 7.06-7.09 (t, J=7.5 Hz, 1H), 6.95 (s, 1H),6.48-6.55 (m, 1H), 4.57-4.61 (m, 1H), 3.41-3.62 (m, 6H), 2.69-3.14 (m,7H), 2.11-2.19 (m, 8H), 1.73-1.77 (m, 2H).

Example 57:(S)-2-(4-(5-(4-(5-fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-117

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1:(S)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

To a solution of(S)-2-(4-(5-(3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(3.5 g, 7.82 mmol) in DCM (100 mL) was added TEA (5.4 mL, 39.1 mmol) andDMAP (191 mg, 1.56 mmol). The mixture was cooled to 0° C., and TBSCl(4.71 g, 31.28 mmol) was added. The resulting mixture was warmed to rt,and stirred for 20 h. Then the reaction mixture was quenched withsaturated aqueous NH₄Cl solution (30 mL) and washed with water (50 mL×2)and brine (50 mL). The organic phase was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel to give(S)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(3.3 g, 5.87 mmol, 75.11%) as a pale yellow solid. ESI-MS (EI⁺, m/z):562.3 [M+H]⁺.

Step 2:(S)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)-4-(5-fluoropyridin-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

To a solution of(S)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(200 mg, 0.35 mmol) and 2-bromo-5-fluoropyridine (188 mg, 1.07 mmol) intoluene (10 mL) was added Pd[(t-Bu)₃P]₂ (18.19 mg, 0.035 mmol) andtBuONa (68.42 mg, 0.71 mmol). The mixture was stirred at 80° C. for 16 hunder nitrogen. The resulting reaction mixture was concentrated invacuum and the residue was purified by column chromatography on silicagel to give(S)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)-4-(5-fluoropyridin-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(300 mg, crude) as a yellow oil which was used for the next stepdirectly. ESI-MS (EI+, m/z): 657.2 [M+H]⁺.

Step 3:(S)-2-(4-(5-(4-(5-fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

To a solution of(S)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)-4-(5-fluoropyridin-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(300 mg, crude) in THF (5 mL) was added TBAF (1M in THF, 1.2 mL). Themixture was stirred at rt for 2 h. The resulting mixture was dilutedwith EtOAc (200 mL), and washed with water (50 mL×2) and brine (50 mL).The organic phase was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified via preparative HPLC to give(S)-2-(4-(5-(4-(5-fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrileI-117 (93.4 mg, 0.17 mmol, 48.39% for two steps) as a white solid.ESI-MS (EI⁺, m/z): 543.3 [M+H]+. ¹H NMR (400 MHz, CDCl₃) δ: 7.98-8.01(dd, J=2.8 Hz, J₂=8.0 Hz, 1H), 7.46-7.57 (m, 2H), 7.29-7.30 (m, 1H),6.94-7.04 (m, 3H), 6.50-6.66 (m, 2H), 4.51-4.85 (m, 2H), 2.99-3.88 (m,15H), 2.12-2.23 (m, 8H).

Example 58:(S)-2-(4-(5-(4-(3-fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-106

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

The procedure for(S)-2-(4-(5-(4-(3-fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrilewas similar to example 57. ESI-MS (EI⁺, m/z): 543.3 [M+H]⁺. ¹H-NMR (500MHz, CDCl₃) δ: 7.91-7.94 (dd, J₁=4.5 Hz, J₂=12.5 Hz, 1H), 7.56 (d, J=8.0Hz, 1H), 7.46-7.49 (m, 1H), 7.29-7.31 (m, 1H), 6.90-7.05 (m, 3H),6.42-6.52 (m, 1H), 3.87-4.75 (m, 5H), 3.22-3.60 (m, 9H), 2.96-3.01 (m,2H), 2.11-2.26 (m, 8H), 1.76-1.78 (m, 2H).

Example 59:2-(4-(4-Cyano-5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-methylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-86

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 5-Bromo-4-cyano-2-methylbenzoic Acid

To a solution of 4-cyano-2-methylbenzoic acid (2 g, 12.42 mmol) in TFA(50 mL) was added NBS (4.42 g, 24.82 mmol). The mixture was stirred at80° C. for 20 h. The resulting mixture was poured into water (300 mL)and stirred for 20 min at rt. The precipitate was collected byfiltration and dried to give 5-bromo-4-cyano-2-methylbenzoic acid (1 g,crude) as a white solid which was used for next step directly. ESI-MS(EI+, m/z): 239.9 [M+H]⁺.

Step 2: Methyl 5-bromo-4-cyano-2-methylbenzoate

To a solution of 5-bromo-4-cyano-2-methylbenzoic acid (850 mg, crude) inMeOH (10 mL) was added SOCl₂ (0.33 mL, 4.6 mmol) at 0° C. Then themixture was stirred at 60° C. for 16 h. The resulting mixture was cooledand concentrated. The residue was purified via preparative HPLC to givemethyl 5-bromo-4-cyano-2-methylbenzoate (320 mg, 1.26 mmol, 10.67% fortwo steps) as a white solid.

Step 3: Methyl4-cyano-5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-methylbenzoate

To a solution of 5-bromo-4-cyano-2-methylbenzoate (300 mg, 1.18 mmol)and 2-(4-aminopiperidin-1-yl)benzonitrile (475 mg, 2.36 mmol) in toluene(15 mL) was added Pd₂(dba)₃ (108 mg, 0.12 mmol), BrettPhos (127 mg, 0.24mmol) and Cs₂CO₃ (769 mg, 2.36 mmol). The mixture was stirred at 80° C.for 5 h under nitrogen. The resulting mixture was concentrated undervacuum and the residue was purified by column chromatography on silicagel to give methyl 4-cyano-5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-methylbenzoate (210 mg, 0.56 mmol, 47.53%) as ayellow oil. ESI-MS (EI+, m/z): 375.1 [M+H]⁺.

Step 4: 4-Cyano-5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-methylbenzoicAcid

The procedure for4-cyano-5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-methylbenzoic acidwas the same as example 52.

Step 5:2-(4-(4-Cyano-5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-methylbenzoyl)piperazin-1-yl)benzenesulfonamide

The procedure for2-(4-(4-cyano-5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-methylbenzoyl)piperazin-1-yl)benzenesulfonamidewas generic amide coupling method B. ESI-MS (EI+, m/z): 584.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ: 8.02-8.04 (dd, _(J)=1.2 Hz, J₂=7.6 Hz, 1H),7.56-7.63 (m, 2H), 7.47-7.52 (m, 1H), 7.34-7.39 (m, 2H), 7.28 (s, 1H),7.01-7.05 (m, 2H), 6.55 (s, 1H), 5.51 (s, 2H), 4.51 (d, J=7.6 Hz, 1H),2.99-3.61 (m, 12H), 2.21 (s, 5H), 1.79-1.85 (m, 2H).

Example 60:2-(4-(5-(1-(2-cyanophenyl)pyrrolidin-3-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-131

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 2-(3-aminopyrrolidin-1-yl)benzonitrile

A mixture of 2-fluorobenzonitrile (2 g, 16.51 mmol), pyrrolidin-3-amine(2.13 g, 24.77 mmol) and K₂CO₃ (6.85 g, 49.53 mmol) in DMF (20 mL) washeated at 80° C. for 5 h. H₂O (20 mL) and EtOAc (20 mL) was added, theorganic phase was separated and the aqueous was further extracted withEtOAc (20 mL×2). The combined extracts were washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated and the residuewas purified by silica gel chromatography (DCM/MeOH=30/1-20/1) to afford2-(3-aminopyrrolidin-1-yl)benzonitrile (2.5 g, 12.28 mmol, 74% yield) asa yellow oil. ESI-MS (EI⁺, m/z): 188.2 [M+H]⁺.

Step 2: methyl5-(1-(2-cyanophenyl)pyrrolidin-3-ylamino)-2,4-dimethylbenzoate

A mixture of 2-(3-aminopyrrolidin-1-yl)benzonitrile (385 mg, 2.06 mmol),methyl 5-bromo-2,4-dimethyl-benzoate (500.79 mg, 2.06 mmol), Pd₂(dba)₃(94.32 mg, 103 umol), BrettPhos (110.57 mg, 206 umol), and sodiumtert-butoxide (395.93 mg, 4.12 mmol) in toluene (30 mL) was heated at80° C. under N₂ atmosphere for 6 h. The reaction mixture wasconcentrated and purified via preparative HPLC to afford methyl5-[[1-(2-cyanophenyl)pyrrolidin-3-yl]amino]-2,4-dimethyl-benzoate (540mg, 1.55 mmol, 75% yield) as a slight oil. ESI-MS (EI⁺, m/z): 350.0[M+H]⁺.

Step 3: 5-(1-(2-cyanophenyl)pyrrolidin-3-ylamino)-2,4-dimethylbenzoicAcid

A mixture of methyl5-[[1-(2-cyanophenyl)pyrrolidin-3-yl]amino]-2,4-dimethyl-benzoate (540mg, 1.55 mmol) and NaOH (620 mg, 15.50 mmol) in THF (10 mL) and H₂O (4mL) was heated at 80° C. for 24 h. The reaction mixture was cooled andacidified to pH=1-2 by added IM HCl, EtOAc (20 mL) was added and theorganic phase was separated, the aqueous was further extracted withEtOAc (20 mL×3). The combined extracts were washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified via preparative HPLC to afford5-[[1-(2-cyanophenyl)pyrrolidin-3-yl]amino]-2,4-dimethyl-benzoic acid(340 mg, 1.01 mmol, 65% yield) as a white solid. ESI-MS (EI⁺, m/z):336.0 [M+H]⁺.

Step 4:2-(4-(5-(1-(2-cyanophenyl)pyrrolidin-3-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-[4-[5-[[1-(2-cyanophenyl)pyrrolidin-3-yl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamideI-131 as a white solid. ESI-MS (EI⁺, m/z): 559.3 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.04 (d, J=1.5 Hz, 1H), 8.03-8.01 (m, 1H), 7.61-7.33 (m,4H), 6.93 (s, 1H), 6.72-6.65 (m, 2H), 6.47 (d, J=10.0 Hz, 1H), 5.55 (s,2H), 4.21-4.12 (m, 2H), 3.91 (br, 1H), 3.81-3.18 (m, 6H), 3.02-2.96 (m,3H), 2.39 (br, 1H), 2.21 (s, 3H), 2.11-2.04 (m, 4H).

Example 61:(R)-2-(4-(5-(3-(Hydroxymethyl)-4-o-tolylpiperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-112

The procedure for(R)-2-(4-(5-(3-(Hydroxymethyl)-4-o-tolylpiperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrilewas similar to example 57.

ESI-MS (EI⁺, m/z): 538.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.57 (d,J=7.5 Hz, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.25-7.11 (m, 2H), 7.10-6.97 (m,4H), 6.93 (s, 1H), 6.56-6.48 (m, 1H), 4.51-4.16 (m, 1H), 3.91-2.91 (m,13H), 2.85-2.66 (m, 1H), 2.35-2.16 (m, 9H), 2.13 (s, 3H).

Example 62:(S)-2-(4-(5-(3-(Hydroxymethyl)-4-o-tolylpiperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-107

The procedure for(S)-2-(4-(5-(3-(Hydroxymethyl)-4-o-tolylpiperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrilewas similar to example 57. ESI-MS (EI⁺, m/z): 538.0 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 7.57 (d, J=7.5 Hz, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.25-7.11(m, 2H), 7.10-6.97 (m, 4H), 6.93 (s, 1H), 6.56-6.48 (m, 1H), 4.51-4.16(m, 1H), 3.91-2.91 (m, 13H), 2.85-2.66 (m, 1H), 2.35-2.16 (m, 9H), 2.13(s, 3H).

Example 63:(R)-2-(4-(5-(3-(Hydroxymethyl)-4-(6-methylpyridin-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-101

The procedure for(R)-2-(4-(5-(3-(Hydroxymethyl)-4-(6-methylpyridin-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrilewas similar to example 57.

ESI-MS (EI⁺, m/z): 539.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d,J=7.6 Hz, 1H), 7.50-7.36 (m, 2H), 7.05-6.98 (m, 2H), 6.94 (s, 1H),6.56-6.41 (m, 3H), 4.77-4.68 (m, 1H), 4.39 (br, 1H), 3.92-3.71 (m, 3H),3.58-3.23 (m, 8H), 3.15-2.96 (m, 3H), 2.37 (s, 3H), 2.22-2.12 (m, 9H).

Example 64:(S)-2-(4-(5-(3-(Hydroxymethyl)-4-(6-methylpyridin-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile,I-102

The procedure for(S)-2-(4-(5-(3-(Hydroxymethyl)-4-(6-methylpyridin-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrilewas similar to example 57.

ESI-MS (EI⁺, m/z): 539.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d,J=7.6 Hz, 1H), 7.50-7.36 (m, 2H), 7.05-6.98 (m, 2H), 6.94 (s, 1H),6.56-6.41 (m, 3H), 4.77-4.68 (m, 1H), 4.39 (br, 1H), 3.92-3.71 (m, 3H),3.58-3.23 (m, 8H), 3.15-2.96 (m, 3H), 2.37 (s, 3H), 2.22-2.12 (m, 9H).

Example 65:2-(4-(3-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide,I-15

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: Methyl3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoate

To a mixture of methyl 3-bromo-2,4,6-trimethyl-benzoate (2 g, 7.78 mmol)and 2-(4-amino-1-piperidyl)benzonitrile (1.88 g, 9.34 mmol) in toluene(50 mL) was added BINAP (484.44 mg, 778 umol) and sodium tert-butoxide(1.50 g, 15.56 mmol). The mixture was degassed for 3 mins, thenPd₂(dba)₃ (712.43 mg, 778 umol) was added, and the resulting mixture wasdegassed for 3 mins then kept stirring at 80° C. for 18 h under N₂. Themixture was filtered and the solvent removed. The residue was purifiedby CombiFlash® (UV254, silica gel, 40 g, EtOAc/PE from 20%˜50%) to givethe product methyl3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoate (1.85g, 4.90 mmol, 62.99% yield) as yellow solid. ESI-MS (EI⁺, m/z): 378.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.55 (dd, J=7.8, 1.4 Hz, 1H),7.49-7.42 (m, 1H), 7.01-6.96 (m, 2H), 6.86 (s, 1H), 3.90 (s, 3H), 3.57(d, J=12.3 Hz, 2H), 2.99 (s, 1H), 2.90 (s, 1H), 2.82-2.74 (m, 2H), 2.26(s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 2.09-2.01 (m, 2H), 1.69 (qd,J=12.1, 3.6 Hz, 2H).

Step 2: 3-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoicAcid

A mixture of methyl3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoate (650mg, 1.72 mmol) in DCM (6 mL) was cooled to −60° C. and boron tribromide(1 M, 4.30 mL) was added. The resulting mixture was kept stirring at 30°C. for 1 h. The mixture was poured into ice-water, and the pH wasadjusted to 4 with sat. Na₂CO₃ and extracted with DCM (40 mL×3). Theorganic layer was dried over Na₂SO₄ for 20 mins, filtrated andconcentrated in vacuo to give the product3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoic acid(510 mg, 1.40 mmol, 81.58% yield) as a yellow solid. ESI-MS (EI⁺, m/z):364.4 [M+H]⁺.

Step 3:2-(4-(3-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-(4-(3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamideI-15 as white solid. ESI-MS (EI⁺, m/z): 588.3 [M+H]⁺. ¹H NMR (400 MHz,MeOD-d₄) δ 8.53 (dd, J=4.8, 1.8 Hz, 1H), 8.34 (dd, J=7.8, 1.8 Hz, 1H),7.61 (dd, J=7.7, 1.5 Hz, 1H), 7.54 (d, J=7.4 Hz, 1H), 7.32 (dd, J=7.8,4.8 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.07 (t, J=7.5 Hz, 1H), 6.97 (s,1H), 4.09-3.99 (m, 2H), 3.58 (d, J=11.9 Hz, 2H), 3.49-3.42 (m, 2H),3.40-3.34 (m, 2H), 3.19 (dd, J=10.9, 6.8 Hz, 2H), 3.11-3.00 (m, 1H),2.84 (dd, J=20.3, 10.8 Hz, 2H), 2.33 (s, 3H), 2.27 (s, 3H), 2.22 (s,3H), 2.02 (t, J=13.0 Hz, 2H), 1.84-1.70 (m, 2H).

Example 66:2-(4-(3-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)-6-fluorobenzenesulfonamide,I-14

Procedures and Characterization:

The procedure was similar to example 65.

The analysis method was following Method B and the separation method wasfollowing Method D.

(S)-(4-((4-(3-chloropyridin-2-yl)piperazin-1-yl)methyl)-1,5-dimethyl-1H-pyrrol-2-yl)(4-(3,4-difluorophenyl)-2-methylpiperazin-1-yl)methanone

ESI-MS (EI⁺, m/z): 604.9 [M+H]⁺. ¹H NMR (500 MHz, MeOD-d₄) δ 7.63-7.51(m, 3H), 7.27 (d, J=8.2 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.11-7.03 (m,2H), 6.96 (s, 1H), 3.58 (d, J=12.1 Hz, 2H), 3.46-3.39 (m, 2H), 3.12-3.02(m, 2H), 2.85 (dd, J=22.8, 10.9 Hz, 2H), 2.33 (s, 3H), 2.27 (s, 3H),2.22 (s, 3H), 2.06-1.95 (m, 2H), 1.84-1.71 (m, 2H).

Example 67:3-(4-(3-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-2-sulfonamide, I-2

Procedures and Characterization:

The procedure was The procedure was similar to example 65.

The analysis method was following Method B and the separation method wasfollowing Method D.

3-(4-(3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-2-sulfonamide

ESI-MS (EI⁺, m/z): 588.3 [M+H]⁺. ¹H NMR (400 MHz, MeOD-d₄) δ 8.53 (dd,J=4.8, 1.8 Hz, 1H), 8.34 (dd, J=7.8, 1.8 Hz, 1H), 7.61 (dd, J=7.7, 1.5Hz, 1H), 7.54 (d, J=7.4 Hz, 1H), 7.32 (dd, J=7.8, 4.8 Hz, 1H), 7.16 (d,J=8.3 Hz, 1H), 7.07 (t, J=7.5 Hz, 1H), 6.97 (s, 1H), 4.09-3.99 (m, 2H),3.58 (d, J=11.9 Hz, 2H), 3.49-3.42 (m, 2H), 3.40-3.34 (m, 2H), 3.19 (dd,J=10.9, 6.8 Hz, 2H), 3.11-3.00 (m, 1H), 2.84 (dd, J=20.3, 10.8 Hz, 2H),2.33 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 2.02 (t, J=13.0 Hz, 2H),1.84-1.70 (m, 2H).

Example 68:2-(4-(5-(1-(2-Methoxyphenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-128

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: tert-Butyl (1-(2-methoxyphenyl)piperidin-4-yl)carbamate

A mixture of I-bromo-2-methoxy-benzene (2 g, 10.69 mmol), tert-butylN-(4-piperidyl) carbamate (2.36 g, 11.76 mmol), BrettPhos (573.81 mg,1.07 mmol) and cesium carbonate (6.97 g, 21.38 mmol) in toluene (35 mL)was degassed for 3 mins. Then Pd₂ (dba)₃ (978.90 mg, 1.07 mmol) wasadded and the mixture degassed for 3 mins again. The mixture was keptstirring at 90° C. for 5 h. The mixture was diluted with DCM (60 mL),filtered and concentrated. The residue was purified by CombiFlash®(silica gel, 40 g, UV254, EA/PE from 0%-40%) to give the producttert-butyl N-[1-(2-methoxyphenyl)-4-piperidyl]carbamate (1.86 g, 6.07mmol, 56.79% yield) as yellow solid. ESI-MS (EI⁺, m/z): 307.2 [M+H]⁺. ¹HNMR (500 MHz, MeOD-d₄) δ 7.01 (d, J=7.5 Hz, 2H), 6.97-6.93 (m, 1H),6.92-6.88 (m, 1H), 3.87 (s, 3H), 3.52-3.42 (m, 1H), 3.38 (d, J=12.3 Hz,2H), 2.67 (td, J=11.8, 2.0 Hz, 2H), 1.95 (d, J=11.8 Hz, 2H), 1.67 (qd,J=11.6, 3.7 Hz, 2H), 1.47 (s, 9H).

Step 2: 1-(2-Methoxyphenyl)piperidin-4-amine

A mixture of tert-butyl N-[1-(2-methoxyphenyl)-4-piperidyl]carbamate(1.86 g, 6.07 mmol) in HCl (4 M in 1,4-dioxane, 19.77 mL) was keptstirring at 23° C. for 3 h. The solvent was removed, the residue wasadjusted to pH 10 with sat. Na₂CO₃ and extracted with a mixed solventsystem MeOH/DCM (1:3) (30 mL×3). The organic layer was washed with H₂O(20 mL×2), dried over Na₂SO₄ for 20 mins, filtrated and concentratedunder vacuum to give the product 1-(2-methoxyphenyl)piperidin-4-amine(860 mg, 4.17 mmol, 68.68% yield) as a yellow solid. ESI-MS (EI⁺, m/z):207.3 [M+H]⁺.

Step 3: Methyl5-(1-(2-methoxyphenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate

A mixture of methyl 5-bromo-2,4-dimethyl-benzoate (785.66 mg, 3.23mmol), 1-(2-methoxyphenyl)piperidin-4-amine (800 mg, 3.88 mmol) intoluene (25 mL) was added BINAP (201.24 mg, 323.19 umol) and sodiumtert-butoxide (621.16 mg, 6.46 mmol). The mixture was degassed for 3mins, then, Pd₂ (dba)₃ (295.95 mg, 323.19 umol) was added. The resultingmixture was degassed for 3 mins. After that, the mixture was keptstirring at 90° C. for 18 h under N₂. The mixture was diluted with EtOAc(60 mL), filtrated and concentrated in vacuo, the residue was purifiedby CombiFlash® (UV254, silica gel, 40 g, EA/PE from 0% to 40% to givethe desired product methyl5-[[1-(2-methoxyphenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate (189mg, 512.93 umol, 15.87% yield) as a yellow solid. ESI-MS (EI⁺, m/z):369.3 [M+H]⁺. ¹H NMR (500 MHz, MeOD-d₄) δ 7.24 (s, 1H), 7.08-7.01 (m,2H), 6.99-6.95 (m, 2H), 6.93 (td, J=7.6, 1.5 Hz, 1H), 3.89 (s, 3H), 3.87(s, 3H), 3.52-3.40 (m, 3H), 2.78 (td, J=11.8, 2.1 Hz, 2H), 2.43 (s, 3H),2.19 (s, 3H), 2.16 (d, J=12.6 Hz, 2H), 1.73 (td, J=14.3, 3.6 Hz, 2H).

Step 4: 5-(1-(2-Methoxyphenyl)piperidin-4-ylamino)-2,4-dimethylbenzoicAcid

A mixture of methyl5-[[1-(2-methoxyphenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate (170mg, 461.37 umol) and LiOH.H₂O (193.77 mg, 4.61 mmol) in water (2 mL) andMeOH (7 mL) was kept stirring at 60° C. for 4 h. Methanol was removed,the pH adjusted to 4 with 4 N HCl aqueous solution, extracted with DCM(25 mL×3) and washed with water (10 mL×2). The organic layer was driedover Na₂SO₄ for 20 min, filtered and concentrated under reduced pressureto give the desired product5-[[1-(2-methoxyphenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoic acid(140 mg, 394.99 umol, 85.61% yield) as white solid. ESI-MS (EI⁺, m/z):355.1 [M+H]⁺.

Step 5:2-(4-(5-(1-(2-Methoxyphenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to give the desire product2-[4-[5-[[1-(2-methoxyphenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamideI-128 (93 mg, 160.97 umol, 47.55% yield) as white solid. ESI-MS (EI⁺,m/z): 578.3 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.75-7.83 (m, 1H),7.63-7.58 (m, 1H), 7.56 (d, J=7.1 Hz, 1H), 7.37-7.31 (m, 1H), 6.96 (s,2H), 6.95-6.90 (m, 3H), 6.89-6.85 (m, 2H), 6.42 (s, 1H), 4.42 (d, J=8.4Hz, 1H), 3.84 (s, 2H), 3.77 (s, 3H), 3.42-3.39 (m, 5H) 3.02-2.71 (m,6H), 2.09 (d, J=1.9 Hz, 6H), 1.99 (d, J=11.0 Hz, 2H), 1.65 (dd, J=20.2,10.4 Hz, 2H).

Example 69:2-(4-(2,4-Dimethyl-5-(1-m-tolylpiperidin-4-ylamino)benzoyl)piperazin-1-yl)benzenesulfonamide,I-129

The procedure was similar to example 68.

The analysis method was following Method B and the separation method wasfollowing Method D.

2-(4-(2,4-dimethyl-5-(1-m-tolylpiperidin-4-ylamino)benzoyl)piperazin-1-yl)benzenesulfonamide

ESI-MS (EI⁺, m/z): 562.3 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (dd,J=7.9, 1.5 Hz, 1H), 7.60 (dd, J=11.3, 4.0 Hz, 1H), 7.56 (d, J=7.1 Hz,1H), 7.35 (t, J=7.5 Hz, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.97 (s, 2H), 6.86(s, 1H), 6.74 (dd, J=13.2, 5.0 Hz, 2H), 6.56 (d, J=7.5 Hz, 1H), 6.43 (s,1H), 4.43 (d, J=8.3 Hz, 1H), 3.84 (dd, J=17.4, 9.6 Hz, 2H), 3.73-3.62(m, 2H), 3.51-3.42 (m, 1H), 3.38 (dt, J=8.7, 4.5 Hz, 2H), 3.08-2.91 (m,2H), 2.91-2.76 (m, 4H), 2.24 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 1.96(dd, J=13.0, 2.0 Hz, 2H), 1.61-1.49 (m, 2H).

Example 70:2-(4-(2,4-Dimethyl-5-(1-o-tolylpiperidin-4-ylamino)benzoyl)piperazin-1-yl)benzenesulfonamide,I-108

The procedure was similar to

The analysis method was following Method B example 68.and the separationmethod was following Method D.

2-(4-(2,4-dimethyl-5-(1-o-tolylpiperidin-4-ylamino)benzoyl)piperazin-1-yl)benzenesulfonamide

ESI-MS (EI⁺, m/z): 562.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 7.87 (d,J=6.6 Hz, 1H), 7.65-7.53 (m, 2H), 7.34 (t, J=7.2 Hz, 1H), 7.15 (t, J=7.0Hz, 2H), 7.04 (d, J=7.6 Hz, 1H), 6.95 (dd, J=14.3, 6.4 Hz, 3H), 6.87 (s,1H), 6.43 (s, 1H), 4.47 (d, J=7.9 Hz, 1H), 3.84 (s, 2H), 3.39 (s, 2H),3.16-2.61 (m, 9H), 2.25 (s, 3H), 2.09 (s, 6H), 2.06-1.96 (m, 2H),1.74-1.58 (m, 2H).

Example 71:2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2-fluoro-4-methylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-113

Procedures and Characterization:

The analysis method was following Method A and the separation method wasfollowing Method C.

Step 1: 5-Bromo-2-fluoro-4-methylbenzoic Acid

To a solution of 2-fluoro-4-methylbenzoic acid (5 g, 32.44 mmol) inconc. H₂SO₄ (20 mL) was added NBS (6.06 g, 34.06 mmol). The resultingmixture was poured into ice-water (100 mL) after stirring for 1 h, theproduct precipitated as a white solid. The solid was collected byfiltration and was dissolved in dichloromethane (50 mL) and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto afford 5-bromo-2-fluoro-4-methyl-benzoic acid (5.10 g, 21.89 mmol,67% yield). ESI-MS (EI+, m/z): 233.0 [M+H]⁺.

Step 2: Methyl 5-bromo-2-fluoro-4-methylbenzoate

5-bromo-2-fluoro-4-methylbenzoic acid (5.10 g, 21.43 mmol) was dissolvedin HCl-MeOH (3 M, 50 mL) and the solution was stirred at 70° C. for 12h. The solvent was removed and the product was attained without furtherpurification. ESI-MS (EI+, m/z): 246.9 [M+H]⁺.

Step 3: Methyl5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-fluoro-4-methylbenzoate

A mixture of methyl 5-bromo-2-fluoro-4-methylbenzoate (1 g, 4.05 mmol),Pd₂(dba)₃ (185.49 mg, 202.50 umol), BrettPhos (128.99 mg, 202.50 umol),tBuONa (777.60 mg, 8.10 mmol) and 2-(4-amino-1-piperidyl)benzonitrile(1.63 g, 8.10 mmol) in dioxane (30 mL) was heated at 80° C. under N₂ for17 h. After cooling to rt, the reaction mixture was diluted with 30 mLwater and extracted with ethyl acetate. The organic layer was collectedand concentrated. Then desired product, methyl 5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-fluoro-4-methylbenzoate (230 mg, 625.99 umol,15.46% yield), was obtained as a yellow oil after purification by columnchromatography. ESI-MS (EI+, m/z): 368.0 [M+H]⁺.

Step 4:5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2-fluoro-4-methylbenzoic Acid

Methyl5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-fluoro-4-methylbenzoate (230mg, 625.99 umol) was dissolved in a mixture of aqueous LiOH (2 M, 20 mL)and MeOH (30 mL). The solution was heated to 60° C. for 2 h. Then LC-MSanalysis showed the reaction proceeded smoothly. The solvent was cooledto rt and the pH value was adjusted to 7. Then the solvent was extractedwith EtOAc and concentrated to yield the product without furtherpurification. ESI-MS (EI+, m/z): 354.2 [M+H]⁺.

Step 5:2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2-fluoro-4-methylbenzoyl)piperazin-1-yl)benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-(4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-fluoro-4-methylbenzoyl)piperazin-1-yl)benzenesulfonamideI-113 as a white solid. MS (EI⁺, m/z): 576.8 [M+H]⁺. 1H NMR (500 MHz,CDCl₃) δ 8.03 (dd, J=7.9, 1.3 Hz, 1H), 7.64-7.55 (m, 2H), 7.50 (t, J=7.9Hz, 1H), 7.43-7.33 (m, 2H), 7.03 (t, J=8.1 Hz, 2H), 6.90 (d, J=9.6 Hz,1H), 6.81 (s, 1H), 3.67-3.45 (m, 5H), 3.20-3.17 (m, 9H), 2.96 (t, J=11.3Hz, 3H), 2.22 (s, 4H).

Example 72:2-(4-(3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,6-dimethylbenzoyl)piperazin-1-yl)-6-fluorobenzenesulfonamide, I-87

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 3-Bromo-2,6-dimethylbenzoic Acid

To a solution of 2,6-dimethylbenzoic acid (2 g, 13.32 mmol) intrifluoroacetic acid (20 mL) was added NBS (2.37 g, 13.32 mmol), andthen heated to 50° C. for 16 h. The reaction was monitored by LCMS andpoured into ice water (50 g) when the reaction was complete to a form asolid precipitate which was filtered and dried to obtain3-bromo-2,6-dimethyl-benzoic acid (2.30 g, 10.04 mmol, 75.38%). MS (EI⁺,m/z): 228.98 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 7.50 (d, J=8.2 Hz, 1H),7.01 (d, J=8.2 Hz, 1H), 2.40 (s, 3H), 2.30 (s, 3H).

Step 2: Methyl 3-bromo-2,6-dimethylbenzoate

To a solution of 3-bromo-2,6-dimethyl-benzoic acid (2.20 g, 9.60 mmol)in DMF (30 mL) was added iodomethane (2.04 g, 14.41 mmol, 896.84 uL),K₂CO₃ (2.65 g, 19.21 mmol), and then stirred at rt for 16 h. Thereaction was monitored by LCMS, when the reaction was done, ethylacetate (100 mL) and water (100 mL) was added, the organic layerseparated, and washed with water (100 mL×3) and brine (80 mL), dried andconcentrated to afford methyl 3-bromo-2,6-dimethyl-benzoate (2.30 g,9.46 mmol, 98.55%). MS (EI⁺, m/z): 242.99 [M+H]⁺.

Step 3: Methyl3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,6-dimethylbenzoate

To a solution of methyl 3-bromo-2,6-dimethyl-benzoate (2.30 g, 9.46mmol) in toluene (30 mL) was added 2-(4-amino-1-piperidyl)benzonitrile(1.90 g, 9.46 mmol), BINAP (589.12 mg, 946 umol), Pd₂(dba)₃ (433.19 mg,473 umol) and tBuONa (2.73 g, 28.38 mmol), and the reaction mixtureheated to 80° C. for 16 h. The reaction was monitored by LCMS, when thereaction was done, ethyl acetate (100 mL) and water (80 mL) were added,the organic layer separated and washed with water (50 mL×2) and brine(50 mL), dried and concentrated to afford the crude, which was purifiedby SGC (EtOAc/PE=1%-20%) to afford methyl3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,6-dimethyl-benzoate (3 g,8.25 mmol, 87.25%). MS (EI⁺, m/z): 364.19 [M+H]

Step 4: 3-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,6-dimethylbenzoicAcid

To a solution of methyl3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,6-dimethyl-benzoate (100 mg,275.14 umol) in DCM was added BBr₃ (4.05 g, 2.75 mmol, 4.05 mL, 17%purity) at 0° C., and then warmed slowly to rt for 16 h. The reactionwas monitored by LCMS, when no starting material was observed, thereaction was quenched by the addition of ice (20 g). Dichloromethane (50mL) and water (20 mL) was added, the organic layer was separated, driedand concentrated to afford3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,6-dimethyl-benzoic acid (96mg, 274.73 umol, 99.85%), which was used in the next step directly. MS(EI⁺, m/z): 350.18 [M+H]⁺.

Step 5:2-(4-(3-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,6-dimethylbenzoyl)piperazin-1-yl)-6-fluorobenzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-[4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,6-dimethyl-benzoyl]piperazin-1-yl]-6-fluoro-benzenesulfonamide,I-87. MS (EI⁺, m/z): 591.25 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.69 (d,J=7.6 Hz, 1H), 7.63-7.51 (m, 2H), 7.42 (s, 2H), 7.27-7.05 (m, 4H), 6.95(s, 1H), 6.69 (s, 1H), 3.52 (s, 4H), 3.27 (s, 2H), 2.93 (dd, J=28.5,18.2 Hz, 6H), 2.15-1.90 (m, 8H), 1.74 (d, J=12.2 Hz, 2H).

Example 73:2-(4-(3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-difluorobenzoyl)piperazin-1-yl)benzenesulfonamide,I-109

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 2,4-Difluoro-3-iodobenzoic Acid

To a solution of 2,4-difluorobenzoic acid (5 g, 31.63 mmol) in H₂SO₄ (30mL) was added NIS (6.76 g, 30.04 mmol) at 5° C. for 3 h. The reactionmixture was monitored by LCMS, when the reaction was done, it was pouredinto ice-water (100 g), then filtered and recrystallized (50%, EtOH,water) to obtain 2,4-difluoro-5-iodo-benzoic acid (4 g, 14.08 mmol,44.53%). MS (EI⁺, m/z): 284.91 [M+H] ⁺

Step 2: Methyl 2,4-difluoro-3-iodobenzoate

To a solution of 2,4-difluoro-3-iodobenzoic acid (2 g, 8.44 mmol) in DMF(50 mL) was added iodomethane (1.80 g, 12.66 mmol, 788.03 uL), K₂CO₃(2.33 g, 16.88 mmol), and the reaction mixture was stirred at rt for 3h. The reaction mixture was monitored by LCMS, when the reaction wascomplete, ethyl acetate (100 mL) and water (100 mL) were added, theorganic layer was separated and washed with water (100 mL×3) and brine(80 mL), dried and concentrated to afford methyl5-bromo-2,4-difluoro-benzoate (2 g, 7.97 mmol, 94.40%). MS (EI⁺, m/z):298.9 [M+H]⁺.

Step 3: Methyl3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-difluorobenzoate

To a solution of methyl 2,4-difluoro-3-iodo-benzoate (1 g, 3.36 mmol) intoluene (20 mL) was added 2-(4-amino-1-piperidyl)benzonitrile (675.36mg, 3.36 mmol), tris(dibenzylideneacetone)dipalladium(O) (153.63 mg,167.77 umol), BrettPhos (180.09 mg, 335.55 umol), and Cs₂CO₃ (2.19 g,6.71 mmol). The reaction mixture was heated to 70° C. for 16 h. Thereaction mixture was monitored by LCMS, when the reaction was done,ethyl acetate (100 mL) and water (100 mL) were added, the organic layerseparated and washed with water(100 mL) and brine (80 mL), dried andconcentrated to afford methyl3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-difluoro-benzoate (280 mg,753.94 umol, 22.44%). MS (EI⁺, m/z): 372 [M+H]⁺.

Step 4: 3-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4-difluorobenzoicAcid

To a solution of methyl3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-difluoro-benzoate (250 mg,673.16 umol) in THF (5 mL) and water (2.50 mL) was added lithiumhydroxide (161.22 mg, 6.73 mmol), and the reaction mixture was heated to50° C. for 3 h. The reaction mixture was monitored by LCMS, when thereaction was done, the reaction mixture was extracted with EtOAc (50mL), washed with water (30 mL×3) and brine (30 mL), dried, filtered andconcentrated to afford3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-difluoro-benzoic acid (120mg, 335.81 umol, 49.88%). MS (EI⁺, m/z): 358.13 [M+H]⁺.

Step 5:2-(4-(3-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4-difluorobenzoyl)piperazin-1-yl)benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-[4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-difluoro-benzoyl]piperazin-1-yl]benzenesulfonamide,I-109. MS (EI⁺, m/z): 581.21 [M+H]⁺. ¹H NMR (500 MHz, DMSO) δ 7.87 (dd,J=7.9, 1.5 Hz, 1H), 7.69 (dd, J=7.7, 1.6 Hz, 1H), 7.64-7.57 (m, 2H),7.54 (d, J=7.3 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.24-7.15 (m, 2H), 7.07(t, J=7.7 Hz, 1H), 6.98 (s, 2H), 6.83-6.78 (m, 1H), 3.66-3.59 (m, 1H),3.56-3.41 (m, 6H), 2.94 (dd, J=31.6, 20.5 Hz, 6H), 2.01 (d, J=11.0 Hz,2H), 1.69 (d, J=9.7 Hz, 2H).

Example 74:2-(4-(2,4-dichloro-5-(1-(2-cyanophenyl)piperidin-4-ylamino)benzoyl)piperazin-1-yl)benzenesulfonamide, I-125

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 5-Bromo-2,4-dichlorobenzoic Acid

To a solution of 2,4-dichlorobenzoic acid (10 g, 52.35 mmol) inchlorosulfonic acid (50 mL) was added bromine (4.18 g, 26.18 mmol, 1.34mL) and sulfur (83.94 mg, 2.62 mmol). The reaction mixture was heated to70° C. for 16 h. The reaction was monitored by LCMS, when the reactionwas complete, it was cooled and poured on ice (50 g), filtered,dissolved in EtOAc (300 mL), washed with water (200 mL), dried andconcentrated to get 5-bromo-2,4-dichloro-benzoic acid (14 g, 51.87 mmol,99%). MS (EI⁺, m/z): 190.96[M+H]⁺.

Step 2: Methyl 5-bromo-2,4-dichlorobenzoate

To a suspension of 5-bromo-2,4-dichloro-benzoic acid (13 g, 48.16 mmol)in MeOH (200 mL) was added thionyl chloride (11.46 g, 96.32 mmol, 6.99mL), and then heated to 70° C. for 16 h. The reaction was monitored byLCMS, when it showed no started material remaining, the reaction mixturewas directly concentrated to afford methyl 5-bromo-2,4-dichloro-benzoate(12 g, 42.26 mmol, 88%). MS (EI⁺, m/z): 282.88 [M+H]⁺.

Step 3: 2,4-Dichloro-5-(1-(2-cyanophenyl)piperidin-4-ylamino)benzoicAcid

To a solution of methyl 5-bromo-2,4-dichloro-benzoate (1 g, 3.52 mmol)in toluene (20 mL) was added 2-(4-amino-1-piperidyl)benzonitrile (708.47mg, 3.52 mmol), tris(dibenzylideneacetone)dipalladium(O) (161.26 mg, 176umol), BINAP (219.30 mg, 352 umol) and tBuONa (0.68 g, 0.7 mmol). Thereaction mixture was heated to 80° C. for 16 h and monitored by LCMS.When the reaction was complete, ethyl acetate (100 mL) and water (100mL) were added, and the pH was adjusted to 5-6 by aqueous hydrochloricacid (IN) at rt. The organic layer was separated and washed with water(100 mL) and brine (80 mL), dried and concentrated, purified by SGC(MeOH/DCM=1%-10%) to afford methyl2,4-dichloro-5-[[1-(2-cyanophenyl)-4-piperidyl]amino]benzoate (190 mg,469.96 umol, 14%) as a yellow solid. MS (EI⁺, m/z): 390.0 [M+H]⁺.

Step 4:2-[4-[2,4-dichloro-5-[[1-(2-cyanophenyl)-4-piperidyl]amino]benzoyl]piperazin-1-yl]benzenesulfonamide

Followed the amide coupling EDCI/HOBT method to afford2-[4-[2,4-dichloro-5-[[1-(2-cyanophenyl)-4-piperidyl]amino]benzoyl]piperazin-1-yl]benzenesulfonamideI-125 as a white solid. MS (EI⁺, m/z): 613.15 [M+H]⁺.

¹H NMR (500 MHz, DMSO-d6) δ 7.88 (dd, J=7.9, 1.5 Hz, 1H), 7.70 (dd,J=7.7, 1.6 Hz, 1H), 7.61 (dt, J=10.2, 4.9 Hz, 2H), 7.53 (d, J=7.9 Hz,1H), 7.48 (s, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.19 (t, J=6.7 Hz, 1H), 7.08(dd, J=13.0, 5.9 Hz, 1H), 6.99 (d, J=5.9 Hz, 2H), 6.86 (s, 1H), 5.38 (s,1H), 3.70-3.32 (m, 6H), 3.10-2.83 (m, 6H), 2.02 (d, J=12.2 Hz, 2H), 1.79(s, 2H).

Example 75:2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2-methylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-22

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2-methylbenzoic Acid

Pd₂(dba)₃ (183.09 mg, 200 umol), tBuONa (384 mg, 4 mmol) and BINAP(249.07 mg, 400 umol) were added to a mixture of methyl5-bromo-2-methyl-benzoate (458 mg, 2 mmol) and2-(4-amino-1-piperidyl)benzonitrile (402.42 mg, 2 mmol) in toluene (20mL). The mixture was stirred at 90° C. for 1 h under nitrogenatmosphere. After being cooled, the mixture was concentrated to obtain aresidue. The residue was purified via preparative HPLC to afford5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-methylbenzoic acid (40 mg,0.12 mmol, 6%) as a white solid. ESI-MS (EI⁺, m/z): 350.2 [M+1]⁺.

Step 2: 2-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2-methylbenzoyl)piperazin-1-yl)benzenesulfonamide

Following the amide coupling EDCI/HOBT method to afford2-(4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2-methylbenzoyl)piperazin-1-yl)benzenesulfonamide1-22 as a white solid. ESI-MS (EI⁺, m/z): 559.3 [M+1]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.05-8.07 (d, J=7.9, 1.5 Hz, 1H), 7.61-7.65 (t, 1H), 7.58-7.59(d, 1H), 7.49-7.52 (t, 1H), 7.36-7.41 (m, 2H), 7.01-7.06 (m, 3H),6.59-6.61 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 5.56 (s, 2H), 3.44-3.59 (m,6H), 3.19 (s, 2H), 2.97-3.03 (m, 3H), 2.20-2.25 (m, 5H), 1.70-1.73 (m,2H), 1.28-1.31 (m, 2H).

Example 76:3-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)pyridine-2-sulfonamide, I-3

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 3-Fluoropyridine-2-sulfonamide

i-PrMgCl (29.84 mmol) was added dropwise to a solution of2-bromo-3-fluoro-pyridine (3.50 g, 19.89 mmol) in THF (15 mL) and themixture was stirred at 25° C. for 1.5 h. To a solution of SO₂Cl₂ (5.37g, 39.78 mmol) in hexane (100 mL) was slowly added the above mixture at0° C. After stirring for 10 min, the reaction mixture was distilled atreduced pressure and the residue was added to ammonia water (50 mL) at0° C. The mixture was stirred at 25° C. for 1 h. The mixture wasconcentrated to obtain a residue. The residue was purified bychromatography on silica gel (DCM/MeOH=15:1) to obtain3-fluoropyridine-2-sulfonamide (1 g, 5.68 mmol, 28%) as yellow solid.ESI-MS (EI⁺, m/z): 177.1[M+1]+.

Step 2: 3-(Piperazin-1-yl)pyridine-2-sulfonamide

3-Fluoropyridine-2-sulfonamide (900 mg, 5.11 mmol) and piperazine(440.06 mg, 5.11 mmol) were dissolved in acetonitrile (10 mL). Themixture was stirred at 110° C. for 1 h by microwave. The mixture waspurified by chromatography on silica gel (DCM/MeOH=10:1) to obtain3-(piperazin-1-yl) pyridine-2-sulfonamide (1 g, 4.13 mmol, 80%) asyellow oil. ESI-MS (EI⁺, m/z): 243.1 [M+1]⁺.

Step 3:3-(4-(5-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)pyridine-2-sulfonamide

Followed the amide coupling EDCI/HOBt method to obtain3-(4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)pyridine-2-sulfonamide1-3 as a white solid. ESI-MS (EI⁺, m/z): 574.3 [M+1]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.39-8.40 (d, J=4.5, 1.2 Hz, 1H), 7.69-7.71 (d, J=8.2, 1.2 Hz,1H), 7.58-7.60 (d, J=7.7, 1.5 Hz, 1H), 7.49-7.54 (m, 2H), 7.02-7.08 (m,2H), 6.94 (s, 1H), 6.50 (s, 1H), 5.28 (s, 2H), 4.11-4.13 (m, 1H), 3.98-4(m, 2H), 3.17-3.25 (m, 2H), 2.97-3.05 (m, 4H), 2.24-2.229 (m, 2H), 2.22(s, 3H), 2.14 (s, 3H), 1.67-1.82 (m, 2H).

Example 77:2-(4-(6-(1-(2-Cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpyridin-2-ylsulfonyl)piperazin-1-yl)benzenesulfonamide,I-111

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1:2-(4-(6-Bromo-3,5-dimethylpyridin-2-ylsulfonyl)piperazin-1-yl)benzenesulfonamide

i-PrMgCl (29.84 mmol) was added dropwise to a solution of2-bromo-3-fluoro-pyridine (3.50 g, 19.89 mmol) in THF (15 mL) and themixture was stirred at 25° C. for 1.5 h. To a solution of SO₂Cl₂ (5.37g, 39.78 mmol) in hexane (100 mL) was slowly added the above mixture at0° C. After stirring for 10 min, the reaction mixture was distilled atreduced pressure and the residue was added to ammonia water (50 mL) at0° C. The mixture was stirred at 25° C. for 1 h. The mixture wasconcentrated to obtain a residue. The residue was purified bychromatography on silica gel (DCM/MeOH=15:1) to obtain2-(4-(6-bromo-3,5-dimethylpyridin-2-ylsulfonyl) piperazin-1-yl)benzenesulfonamide (1.6 g, 3.27 mmol, 20%) as yellow solid. ESI-MS (EI⁺,m/z): 489.0 [M+1]⁺.

Step 2:2-(4-(6-(1-(2-Cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpyridin-2-ylsulfonyl)piperazin-1-yl)benzenesulfonamide

tBuONa (236.16 mg, 2.46 mmol) and Pd(t-Bu₃P)₂ (62.85 mg, 123 umol) wereadded to a mixture of2-[4-[(6-bromo-3,5-dimethyl-2-pyridyl)sulfonyl]piperazin-1-yl]benzenesulfonamide(600 mg, 1.23 mmol) and 2-(4-amino-1-piperidyl)benzonitrile (247.56 mg,1.23 mmol) in toluene (30 mL). The mixture was stirred at 90° C. for 18h. Then the mixture was concentrated to obtain a residue. The residuewas purified via preparative HPLC to obtain2-(4-(6-(1-(2-cyanophenyl)piperidin-4-ylamino)-3,5-dimethylpyridin-2-ylsulfonyl)piperazin-1-yl)benzenesulfonamideI-111 (25 mg, 0.04 mmol, 3%) as a white solid. ESI-MS (EI⁺, m/z):610.3[M+1]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.85-7.86 (d, J=7.3 Hz, 1H),7.66-7.69 (d, J=7.5 Hz, 1H), 7.62-7.65 (m, 2H), 7.54-7.58 (t, 1H),7.36-7.39 (t, 1H), 7.33 (s, 1H), 7.26-7.28 (d, J=8.3 Hz, 1H), 7.05-7.09(t, 1H), 6.93 (s, 2H), 6.00-6.01 (d, J=7.7 Hz, 1H), 4.06-4.07 (m, 1H),3.49-3.57 (m, 6H), 3.07-3.14 (m, 6H), 2.36 (s, 3H), 2.09-2.13 (m, 5H),1.76-1.84 (m, 2H).

Example 78:(R)-2-(4-(5-(4-(3-Fluoro-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile, I-89

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: (2,6-Difluorophenyl)(methyl)sulfane

n-BuLi (92.03 mmol, 2 M in THF, 46 mL) was added slowly to a solution of1,3-difluorobenzene (10.50 g, 92.03 mmol) in THF (300 mL). The mixturewas stirred at −78° C. for 20 min. Then (methyldisulfanyl) methane(10.40 g, 110.44 mmol) was added to the mixture. The cooling bath wasremoved and the reaction mixture was warmed to 25° C. The reactionmixture was poured onto ice (200 mL) and extracted with EtOAc (300 mL).The organic layer was washed with brine and dried to obtain(2,6-difluorophenyl)(methyl)sulfane (12.6 g, 78.66 mmol, 85%) as acolorless oil.

Step 2: 1,3-Difluoro-2-(methylsulfinyl)benzene

To a suspension of 1,3-difluoro-2-methylsulfanyl-benzene (11 g, 68.67mmol) in DCM (250 mL) at 0° C. was added m-CPBA (12.99 g, 75.54 mmol) ata rate such that the temperature of the reaction mixture did not exceed10° C. over the course of the addition. The reaction mixture was thenallowed to warm to rt followed by stirring at rt overnight. The solutionwas washed with 2 N NaOH (80 mL) and brine (50 mL), then concentrated togive a residue. The residue was purified by flash column (0% to 20% andto 35% of EtOAc in PE) to afford 1,3-difluoro-2-(methylsulfinyl)benzene(10.7 g, 60.7 mmol, 88%) as a colorless oil. ESI-MS (EI⁺, m/z):177.0[M+1].

Step 3: N-Boc-1,3-difluoro-2-(S-methylsulfonimidoyl)benzene

To a suspension of 1,3-difluoro-2-methylsulfinyl-benzene (11 g, 62.44mmol), MgO (10.32 g, 249.76 mmol) and Rh₂(OAc)₄ (827.95 mg, 1.87 mmol)in DCM (200 mL) was added portion-wise PhI(OAc)₂ (40.21 g, 124.88 mmol)and the reaction mixture was stirred at 25° C. for 18 h. The mixture wasfiltered and concentrated to obtain a residue. The residue was dissolvedin DMF, filtered and purified via preparative HPLC to obtainN-Boc-1,3-difluoro-2-(S-methylsulfonimidoyl)benzene (4.5 g, 15.45 mmol,24%) as a brown oil. ESI-MS (EI⁺, m/z): 236.1 [M−55]⁺.

Step 4: 1-(N-Boc-3-fluoro-2-(S-methylsulfonimidoyl) phenyl) piperazine

K₂CO₃ (994.8 mg, 7.2 mmol) was added to a solution of piperazine (341.5mg, 3.96 mmol) and N-Boc-1,3-difluoro-2-(S-methylsulfonimidoyl)benzene(1050 mg, 3.0 mmol) in DMF (25 mL). The mixture was stirred at 110° C.for 1 h. After being cooled, the mixture was purified via preparativeHPLC to obtain1-(N-Boc-3-fluoro-2-(S-methylsulfonimidoyl)phenyl)piperazine (420 mg,1.2 mmol, 32%) as a colorless oil.

Step 5:(R)-2-(4-(5-(4-(3-Fluoro-N-Boc-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

EDCI (96.18 mg, 503.58 umol), HOBt (68.04 mg, 503.58 umol) and DIPEA(108.47 mg, 839.30 umol, 146.58 uL) were added to a solution of(R)-1-(N-Boc-3-fluoro-2-(S-methylsulfonimidoyl)phenyl)piperazine (150mg, 419.65 umol) and5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoic acid(146.64 mg, 419.65 umol) in DMF (4 mL). The mixture was stirred at 25°C. for 1 h. Then the mixture was purified via preparative HPLC to obtain(R)-2-(4-(5-(4-(3-fluoro-N-Boc-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(115 mg, 0.17 mmol, 39%) as a white solid. ESI-MS (EI⁺, m/z):689.3[M+1]⁺.

Step 6:(R)-2-(4-(5-(4-(3-Fluoro-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

TFA (702.01 mg, 6.16 mmol) was added to a solution(R)-2-(4-(5-(4-(3-fluoro-N-Boc-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(115 mg, 166.94 umol) in DCM (5 mL). The mixture was stirred at 25° C.for 1 h. Then the mixture was concentrated to obtain a residue. Theresidue was purified via preparative HPLC to obtain(R)-2-(4-(5-(4-(3-fluoro-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrileI-89 (50 mg, 0.085 mmol, 50%) as a white solid. The stereochemistry wasarbitrarily assigned. ESI-MS (EI⁺, m/z): 589.3 [M+1]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.58-7.60 (d, J=7.7 Hz 1H), 7.46-7.54 (m, 2H), 7.14-7.17 (d,J=8.0 Hz, 1H), 7.01-7.08 (m, 3H), 6.94 (s, 1H), 6.44-6.50 (m, 1H),4.94-5.20 (m, 2H), 2.62-3.63 (m, 16H), 2.14-2.26 (m, 8H), 1.70-1.80 (m,2H).

Example 79:(S)-2-(4-(5-(4-(3-Fluoro-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile, I-88

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1:(S)-2-(4-(5-(4-(3-Fluoro-N-Boc-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

EDCI (96.18 mg, 503.58 umol), HOBt (68.04 mg, 503.58 umol) and DIPEA(108.47 mg, 839.30 umol, 146.58 uL) were added to a solution of(S)-1-(N-Boc-3-fluoro-2-(S-methylsulfonimidoyl)phenyl)piperazine (150mg, 419.65 umol) and5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoic acid(146.64 mg, 419.65 umol) in DMF (4 mL). The mixture was stirred at 25°C. for 1 h. Then the mixture was purified via preparative HPLC to obtain(S)-2-(4-(5-(4-(3-fluoro-N-Boc-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(120 mg, 0.17 mmol, 41%) as a white solid. ESI-MS (EI⁺, m/z): 689.3[M+1]⁺.

Step 2:(S)-2-(4-(5-(4-(3-Fluoro-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile

TFA (732.54 mg, 6.42 mmol) was added to a solution of(S)-2-(4-(5-(4-(3-fluoro-N-Boc-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile(120 mg, 174.20 umol) in DCM (5 mL). The mixture was stirred at 25° C.for 1 h. Then the mixture was concentrated to obtain a residue. Theresidue was purified via preparative HPLC to obtain(S)-2-(4-(5-(4-(3-fluoro-2-(S-methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrileI-88 (30 mg, 0.051 mmol, 29%) as a white solid. The stereochemistry wasarbitrarily assigned. ESI-MS (EI⁺, m/z): 589.3 [M+1]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.58-7.60 (d, J=7.6 Hz, 1H), 7.46-7.53 (m, 2H), 7.15-7.17 (d,J=8.1 Hz, 1H), 7.02-7.08 (m, 3H), 6.94 (s, 1H), 6.43-6.54 (m, 1H),4.86-5.21 (m, 2H), 2.60-3.64 (m, 16H), 2.14-2.26 (m, 8H), 1.68-1.80 (m,2H).

Example 80: Synthesis of(S)-2-amino-5,5,5-trifluoro-4,4-dimethylpentanoic acid and(R)-2-amino-5,5,5-trifluoro-4,4-dimethylpentanoic Acid, I-124

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: methyl3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate

A mixture of methyl 3-bromo-2,4-dimethyl-benzoate (800 mg, 3.29 mmol),2-(4-amino-1-piperidyl)benzonitrile (1.32 g, 6.58 mmol), BrettPhos(353.28 mg, 0.658 mmol), Pd₂(dba)₃ (301 mg, 0.329 mmol) and Cs₂CO₃ (2.14g, 6.58 mmol) in toluene (60 mL) was heated to 100° C. for 24 h, themixture was diluted with EtOAc (100 mL), washed with water (100 mL) andbrine (100 mL), dried (Na₂SO₄), filtered and concentrated under vacuumand purified by chromatography (silica, PE/EA=5:1) to afford methyl3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate (500 mg,605 umol, 18.40% yield, 44% purity) as a brown solid. ESI-MS (EI⁺, m/z):364.0 [M+H]⁺.

Step 2: 3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoicAcid

A solution of methyl3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate (450 mg,1.24 mmol) and LiOH.H₂O (416 mg, 9.92 mmol) in methanol (15 mL) and H₂O(5 mL) was heated to 60° C. for 17 h, the solution was diluted withwater (100 mL), extracted with DCM (50 mL×2), the organic phase wasadjusted PH to 3 with 6M HCl, and then extracted with EtOAc (50 mL×2),dried (Na₂SO₄), filtered and concentrated under vacuum to afford3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoic acid (220mg, 629 umol, 50%, 2 steps) as a brown solid. ESI-MS (EI⁺, m/z): 350.0[M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 7.55-7.60 (m, 2H), 7.45-7.49 (m, 1H),7.08 (d, J=8.0 Hz, 1H), 6.98-7.01 (m, 2H), 3.58 (d, J=12.0 Hz, 2H),3.07-3.09 (m, 1H), 2.80 (t, J=11.2 Hz), 2.58 (s, 3H), 2.35 (s, 3H),2.05-2.07 (m, 2H), 1.69-1.75 (m, 2H).

Step 3:2-[4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamide

Following the amide coupling HATU method to afford2-[4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamideI-124 as a white solid. ESI-MS (EI−, m/z): 572.9 [M+H]⁺. 1H NMR (500MHz, DMSO) δ 7.87 (dd, J=8.0 Hz, 1.5 Hz, 1H), 7.68 (dd, J=7.5, 1.5 Hz,1H), 7.66-7.53 (m, 3H), 7.34 (t, J=7.5 Hz, 1H), 7.20-7.03 (m, 3H), 6.97(m, 2H), 6.85 (m, 1H), 3.95 (m, 2H), 3.51 (d, J=12.0 Hz, 2H), 3.33 (d,J=6.5 Hz, 2H), 3.15-3.20 (m, 1H), 2.97-3.00 (m, 2H), 2.80-2.86 (m, 4H),2.33 (s, 3H), 2.23 (s, 3H), 1.91-1.97 (m, 2H), 1.81-1.82 (m, 2H).

Example 81:3-(4-(3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)pyridine-2-sulfonamide,I-121

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

3-[4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]pyridine-2-sulfonamide

Following the amide coupling EDCI/HOBT method to afford3-[4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]pyridine-2-sulfonamide1-121 as a white solid. ESI-MS (EI+, m/z): 574.3 [M+H]+. 1H NMR (400MHz, DMSO) δ 8.38 (dd, J=4.4, 1.2 Hz, 1H), 7.92 (d, J=7.1 Hz, 1H),7.74-7.46 (m, 4H), 7.05-7.20 (m, 5H), 6.86 (d, J=7.6 Hz, 1H), 3.75-3.90(m, 2H), 3.50-3.53 (m, 2H), 3.09-3.29 (m, 5H), 2.83-2.96 (m, 4H), 2.34(s, 3H), 2.23 (s, 3H), 1.81-2.09 (m, 4H).

Example 82:2-(4-(3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide,I-120

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

2-[4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]pyridine-3-sulfonamide

Following the amide coupling EDCI/HOBT method to afford2-[4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]pyridine-3-sulfonamide1-120 as a white solid. ESI-MS (EI+, m/z): 574.3 [M+H]⁺. ¹H NMR (400MHz, DMSO-d6) δ 8.49 (dd, J=4.4, 1.6 Hz, 1H), 8.23 (dd, J=8.0 Hz, J=1.6Hz, 1H), 7.69 (dd, J=8.0 Hz, J=1.6 Hz, 1H), 7.55-7.58 (m, 1H), 7.26-7.33(m, 3H), 7.05-7.16 (m, 3H), 6.83 (d, J=7.6 Hz, 1H), 3.84-3.87 (m, 2H),3.50-3.53 (m, 2H), 3.26-3.34 (m, 4H), 3.11-3.13 (m, 3H), 2.81-2.84 (m,2H), 2.34 (s, 3H), 2.22 (s, 3H), 1.81-1.94 (m, 4H).

Example 83: (5-(1-(2-chlorophenyl)piperidin-4-ylamino)-2,4-dimethylphenyl) (4-(6-methylpyridin-2-yl)piperazin-1-yl) methanone, I-35

Synthetic Scheme:

Procedures and Characterization:

The analysis method was following Method B and the separation method wasfollowing Method D.

Step 1: 1-(6-methylpyridin-2-yl)piperazine

To a solution of 2-bromo-6-methylpyridine (1 g, 5.81 mmol), piperazine(751.13 mg, 8.72 mmol) in toluene (20 mL) was added Pd₂ (dba)₃ (266.01mg, 290.50 umol), BINAP (180.87 mg, 290.50 umol), tBuONa (558.34 mg,5.81 mmol). The mixture was stirred at 100° C. under N₂ for 17 h. Themixture was added water (20 mL), extracted with DCM (20 mL×3). Theorganic layer was dried and concentrated to give the crude. The crudewas purified by SCG (PE:EA=10:1 to MeOH) to give the1-(6-methylpyridin-2-yl)piperazine (500 mg, 2.82 mmol, 48.55% yield,100% purity) as yellow oil.

Step 2: (5-(1-(2-chlorophenyl) piperidin-4-ylamino)-2,4-dimethylphenyl)(4-(6-methylpyridin-2-yl) piperazin-1-yl) methanone

Following the amide coupling EDCI/HOBT method to obtain(5-(1-(2-chlorophenyl) piperidin-4-ylamino)-2,4-dimethylphenyl)(4-(6-methylpyridin-2-yl) piperazin-1-yl) methanone 1-35 as a whitesolid. ESI-MS (EI⁺, m/z): 518.3 [M+H]⁺.

¹H NMR (500 MHz, CDCl₃) δ 7.41-7.35 (m, 2H), 7.23-7.20 (m, 1H), 7.06 (d,J=7.0 Hz, 1H), 6.98-6.94 (m, 1H), 6.92 (s, 1H), 6.54 (d, J=7.5 Hz, 1H),6.49 (s, 1H), 6.45 (d, J=8.5 Hz, 1H), 3.94-3.91 (m, 2H), 3.62 (t, J=5.5Hz, 1H), 3.48-3.36 (m, 8H), 2.81-2.79 (m, 2H), 2.38 (s, 3H), 2.29-2.20(m, 5H), 2.13 (s, 3H).

Example 84:4-(5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoyl)-1-phenylpiperazine-2-carboxylicAcid, I-39

To a solution of5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid[Intermediate 1] (75 mg, 0.21 mmol) and HATU (85 mg, 0.22 mmol) in DMF(2 ml) was added DIPEA (200 μl, 1.12 mmol). The reaction mixture stirredat rt for 30 mins. 1-phenylpiperazine-2-carboxylic acid dihydrochloride(61 mg, 0.22 mmol) was added and the reaction mixture was stirred at rtfor 5 h. H₂O was added to the reaction mixture and left to stand for 15min. The crude reaction mixture was purified by preparative HPLC[UV-Directed High pH prep method]. The fractions containing product werecombined and concentrated in vacuo to afford the title compound I-39 asa pink solid (51 mg, 42%).

1H NMR (500 MHz, DMSO-d6) δ 7.68 (d, J=7.6 Hz, 1H), 7.58 (t, J=7.6 Hz,1H), 7.22-7.12 (m, 3H), 7.06 (t, J=7.5 Hz, 1H), 6.92-6.78 (m, 3H),6.78-6.62 (m, 1H), 6.42 (s, 1H), 5.05-3.62 (m, 4H), 3.62-3.47 (m, 5H),3.18-2.73 (m, 5H), 2.18-1.97 (m, 8H), 1.85-1.55 (m, 2H). LCMS Method6—Tr=3.27 min (ES+) (M+H)+ 538.3

Example 85:4-(5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoyl)-N-methyl-1-phenylpiperazine-2-carboxamide,I-32

4-(5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoyl)-1-phenylpiperazine-2-carboxylicacid (50 mg, 0.09 mmol) and HATU (40 mg, 0.11 mmol) were dissolved inDMF (1 ml). DIPEA (50 μl, 0.28 mmol) was added and the reaction mixturewas stirred for 30 min. methanamine hydrochloride (15 mg, 0.22 mmol) wasadded and the reaction mixture was sonicated for 20 min then left tostand overnight. The reaction mixture was purified by preparative HPLC[UV-Directed High pH prep method]. The fraction containing product wasreduced in vacuo and dried in a vac oven over night to yield the titlecompound I-32 as a white solid (15 mg, 28%)

1H NMR (250 MHz, DMSO-d6; 353° K) δ 7.77-7.51 (m, 3H), 7.27-7.12 (m,3H), 7.10-7.00 (m, 1H), 6.92-6.71 (m, 4H), 6.44 (s, 1H), 4.26 (d, J=7.9Hz, 1H), 4.13 (s, 1H), 3.56 (d, J=14.1 Hz, 9H), 2.98 (s, 2H), 2.59 (d,J=4.6 Hz, 3H), 2.17-1.99 (m, 8H), 1.82-1.62 (m, 2H).

LCMS Method 6—Tr=4.81 min (ES+) (M+H)+ 551.2

Example 86:4-(5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoyl)-1-phenylpiperazine-2-carboxamide,I-31

4-(5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoyl)-1-phenylpiperazine-2-carboxylicacid [Example 84] (50 mg, 0.09 mmol) and HATU (40 mg, 0.11 mmol) weredissolved in DMF (1 ml). DIPEA (50 μl, 0.28 mmol) was added and thereaction mixture was stirred for 30 min. Formic acid amine (20 mg, 0.32mmol) was added and the reaction mixture was sonicated for 20 min thenleft to stand overnight. The reaction mixture was purified bypreparative HPLC [UV-Directed High pH prep method]. The fractioncontaining product was reduced in vacuo and dried in a vac oven overnight to yield the title compound I-31 as a white solid (21 mg, 40%)

1H NMR (250 MHz, DMSO-d6) δ 7.69-7.50 (m, 2H), 7.28-7.13 (m, 3H),7.12-6.90 (m, 3H), 6.90-6.70 (m, 4H), 6.46 (s, 1H), 4.32-4.08 (m, 2H),4.00-3.31 (m, 9H), 3.02-2.93 (m, 2H), 2.18-2.05 (m, 8H), 1.83-1.62 (m,2H).

LCMS Method 6—Tr=4.67 min (ES+) (M+H)+ 537.2

Example 87:2-[4-({2,4-Dimethyl-5-[4-(pyridazin-3-yl)piperazine-1-carbonyl]phenyl}amino)piperidin-1-yl]benzonitrile,I-70

The title compound was prepared according to the general method employedin [Example 154] below, using5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid[Intermediate 1] (29.79 mg, 0.09 mmol) and 3-(piperazin-1-yl)pyridazine(14 mg, 0.09 mmol) to yield the title compound I-70 as an off-whitepowder (7.0 mg, 17%). 1H NMR (500 MHz, Chloroform-d) δ 8.63 (dd, J=4.5,1.2 Hz, 1H), 7.56 (dd, J=7.7, 1.5 Hz, 1H), 7.50-7.45 (m, 1H), 7.26-7.21(m, 1H), 7.06-6.98 (m, 2H), 6.95-6.92 (m, 2H), 6.48 (s, 1H), 4.03-3.90(m, 2H), 3.76-3.40 (m, 10H), 3.03-2.91 (m, 2H), 2.30-2.17 (m, 5H), 2.14(s, 3H), 1.82-1.64 (m, 2H).

LCMS Method 7—Tr=2.60 min (ES+) (M+H)+ 496.3

Example 88:2-[(3S)-4-(5-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoyl)-3-methylpiperazin-1-yl]-4,5-difluorobenzonitrile,I-69

The title compound was prepared according to the generic method [Example154] using5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid[Intermediate 1] (28 mg, 0.08 mmol) and4,5-difluoro-2-[(3S)-3-methylpiperazin-1-yl]benzonitrile [Intermediate7] (19 mg, 0.08 mmol) to yield a pale yellow solid 1-69 (2.0 mg, 4%).

1H NMR (250 MHz, DMSO-d6) δ 7.96-7.83 (m, 1H), 7.67-7.52 (m, 2H), 7.27(dd, J=12.7, 7.2 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 7.05 (t, J=7.5 Hz,1H), 6.90 (s, 1H), 6.45 (s, 1H), 4.29 (d, J=8.2 Hz, 1H), 3.62-3.45 (m,5H), 3.44-3.21 (m, 6H), 2.15-2.02 (m, 9H), 1.82-1.62 (m, 2H), 1.38 (d,J=6.8 Hz, 3H).

LCMS Method 7—Tr=4.36 min (ES+) (M+H)+ 569.2

Example 89:2-[4-({5-[4-(2-cyanophenyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}(methyl)amino)piperidin-1-yl]benzonitrile,I-68

The title compound was synthesized from5-{[1-(2-cyanophenyl)piperidin-4-yl](methyl)amino}-2,4-dimethylbenzoicacid [Intermediate 9] (35 mg, 0.096 mmol) and2-(piperazin-1-yl)benzonitrile(18 mg, 0.096 mmol) using the methoddescribed below for example 154 to afford the title compound I-68 as astraw glass (10 mg, 19%).

1H NMR (500 MHz, Chloroform-d) δ 7.59 (dd, J=7.7, 1.6 Hz, 1H), 7.56-7.49(m, 2H), 7.44 (td, J=7.9, 7.5, 1.7 Hz, 1H), 7.09-7.05 (m, 2H), 7.02 (d,J=8.2 Hz, 1H), 6.99-6.94 (m, 2H), 6.93 (s, 1H), 4.07-3.98 (m, 2H),3.63-3.54 (m, 2H), 3.54-3.47 (m, 2H), 3.29-3.21 (m, 2H), 3.14-3.07 (m,2H), 2.95-2.85 (m, 1H), 2.83-2.74 (m, 2H), 2.66 (s, 3H), 2.29 (s, 3H),2.26 (s, 3H), 2.00-1.82 (m, 4H), 1.54 (s, 6H).

LCMS Method 6—Tr=4.68 min (ES+) (M+H)⁺ 533

Example 90:2-(4-{[5-(4-{2-[imino(methyl)oxo-λ⁶-sulfanyl]phenyl}piperazine-1-carbonyl)-2,4-dimethylphenyl]amino}piperidin-1-yl)benzonitrile,I-62

To a suspension of tert-butylN-({2-[4-(5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoyl)piperazin-1-yl]phenyl}(methyl)oxo-λ-sulfanylidene)carbamate[Intermediate 13] (440 mg, 0.63 mmol) in DCM (4 mL) was added 4M HCl indioxane (6 mL). The reaction mixture stirred overnight. The reactionmixture was concentrated in vacuo to afford a white solid. The whitesolid was then dissolved in DCM (10 mL) and sat. aq. NaHCO₃(10 mL) andthe mixture stirred at rt for 30 min. After 30 min, the organic phasewas separated dried (MgSO₄), filtered and reduced in vacuo. Theresulting residue was dissolved in acetonitrile/water (3 mL, 4:1) andfreeze dried under vacuum to afford the title compound I-62 as off-whitesolid (340 mg, 90%).

1H NMR (500 MHz, Chloroform-d) δ 8.05 (dd, J=7.8, 1.4 Hz, 1H), 7.62-7.54(m, 2H), 7.53-7.45 (m, 1H), 7.39-7.32 (m, 2H), 7.06-6.98 (m, 2H), 6.92(s, 1H), 6.49 (s, 1H), 3.68-3.27 (m, 10H), 3.25-2.72 (m, 7H), 2.32-2.17(m, 5H), 2.12 (s, 3H), 1.84-1.73 (m, 1H), 1.73-1.62 (m, 1H).

LCMS Method 6—Tr=4.45 min (ES+) (M+H)⁺ 571

Example 91: 2-(4-{[5-(4-{2-[(R orS)-imino(methyl)oxo-λ⁶-sulfanyl]phenyl}piperazine-1-carbonyl)-2,4-dimethylphenyl]amino}piperidin-1-yl)benzonitrile,I-50 Example 92: 2-(4-{[5-(4-{2-[(S orR)-imino(methyl)oxo-λ⁶-sulfanyl]phenyl}piperazine-1-carbonyl)-2,4-dimethylphenyl]amino}piperidin-1-yl)benzonitrile,I-49

2-(4-{[5-(4-{2-[imino(methyl)oxo-λ⁶-sulfanyl]phenyl}piperazine-1-carbonyl)-2,4-dimethylphenyl]amino}piperidin-1-yl)benzonitrile[Example 90] was dissolved in 55 mg/mL in methanol and was then purifiedby chiral HPLC. Combined fractions of the first eluting peak 1 at 9.023min and peak 2 at 11.235 min were then evaporated to near dryness usinga rotary evaporator, transferred into final vessels with DCM, which wasremoved under a stream of nitrogen at 40° C. before being stored in avacuum oven at 40° C. and 5 mbar for 16 h to afford yellow gums. Theyellow gums were dissolved in 4:1 acetonitrile/water (2 ml) andlyophilized, followed by oven drying at 40° C. to obtain the titlecompounds as off white colored powders (116 mg, 42%).

Separation conditions:

-   -   Column Details Lux C4 (21.2 mm×250 mm, 5 um)    -   Column Temperature Ambient    -   Flow Rate 21 mL/min    -   Detector Wavelength 216 nm    -   Injection Volume 325 uL (18 mg)    -   Isocratic Conditions MeOH (0.1% v/v NH3)        Arbitrary Assignment of Stereochemistry

Peak 1: 2-(4-{[5-(4-{2-[(R orS)-imino(methyl)oxo-λ⁶-sulfanyl]phenyl}piperazine-1-carbonyl)-2,4-dimethylphenyl]amino}piperidin-1-yl)benzonitrile

1H NMR (500 MHz, Chloroform-d) δ 8.05 (dd, J=7.8, 1.5 Hz, 1H), 7.62-7.54(m, 2H), 7.52-7.47 (m, 1H), 7.39-7.33 (m, 2H), 7.06-6.98 (m, 2H), 6.92(s, 1H), 6.49 (s, 1H), 3.68-3.23 (m, 10H), 3.24-2.41 (m, 7H), 2.34-2.19(m, 5H), 2.12 (s, 3H), 1.86-1.73 (m, 1H), 1.73-1.65 (m, 1H).

LCMS Method 7—Tr=3.10 min (ES+) (M+H)⁺ 571

Arbitrary Assignment of Stereochemistry

Peak 2: 2-(4-{[5-(4-{2-[(S orR)-imino(methyl)oxo-2⁶-sulfanyl]phenyl}piperazine-1-carbonyl)-2,4-dimethylphenyl]amino}piperidin-1-yl)benzonitrile

1H NMR (500 MHz, Chloroform-d) δ 8.05 (dd, J=7.9, 1.5 Hz, 1H), 7.64-7.52(m, 2H), 7.51-7.46 (m, 1H), 7.38-7.31 (m, 2H), 7.06-6.99 (m, 2H), 6.92(s, 1H), 6.49 (s, 1H), 3.69-3.20 (m, 10H), 3.20-2.31 (m, 7H), 2.29-2.16(m, 5H), 2.12 (s, 3H), 1.85-1.73 (m, 1H), 1.73-1.66 (m, 1H).

LCMS Method 7—Tr=3.10 min (ES+) (M+H)⁺ 571

Example 93: 2-[4-({5-[3R orS-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-41 Example 94: 2-[4-({5-[3S orR-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-40

2-[4-({5-[3-(Hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile[I-63] was dissolved to 40 mg/mL in methanol and was then purified bySFC. Combined fractions of each of peak 1 at 2.514 min and peak 2 at3.447 min were then evaporated to near dryness using a rotaryevaporator, transferred into final vessels with DCM, which was removedunder a stream of nitrogen at 40° C. before being stored in a vacuumoven at 40° C. and 5 mbar for 16 h to afford I-40 and I-41 as clearoils. The oils were lyophilized overnight to give the title compounds aswhite solids.

Separation Conditions:

-   -   Column Details: CHIRALPAK® AS-H (20 mm×250 mm)    -   Column Temperature: 40° C.    -   Flow Rate: 50 ml/min    -   Detector Wavelength: 210 nm    -   Injection Volume: 200 μl (8 mg)    -   Isocratic Conditions: 30:70 MeOH:CO₂ (0.1% v/v NH₃)        The Stereochemistry was Arbitrarily Assigned:

2-[4-({5-[3R orS-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile(53 mg, 24%)

Peak 1 at 2.514 min

¹H NMR (500 MHz, DMSO-d6) δ 7.68 (dd, J=7.7, 1.5 Hz, 1H), 7.61-7.55 (m,1H), 7.23-7.15 (m, 3H), 7.06 (t, J=7.5 Hz, 1H), 6.92-6.83 (m, 3H), 6.73(t, J=7.2 Hz, 1H), 6.41 (s, 1H), 4.78-4.49 (m, 2H), 4.49-4.05 (m, 1H),3.91-3.41 (m, 6H), 3.40-3.32 (m, 3H), 3.30-3.08 (m, 2H), 2.96 (t, J=11.0Hz, 3H), 2.09 (d, J=2.8 Hz, 3H), 2.07-1.99 (m, 4H), 1.77-1.62 (m, 2H).LCMS Method 7—Tr=3.73 min (ES+) (M+H)+ 524.2

2-[4-({5-[3S orR-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile(55 mg, 24%)

Peak 2 at 3.447 min

¹H NMR (500 MHz, DMSO-d6) δ 7.68 (dd, J=7.7, 1.5 Hz, 1H), 7.61-7.55 (m,1H), 7.23-7.14 (m, 3H), 7.06 (t, J=7.5 Hz, 1H), 6.92-6.82 (m, 3H), 6.73(t, J=7.2 Hz, 1H), 6.41 (s, 1H), 4.79-4.50 (m, 2H), 4.49-4.09 (m, 1H),3.71 (d, J=127.7 Hz, 6H), 3.41-3.32 (m, 3H), 3.24-2.87 (m, 4H),2.14-2.00 (m, 8H), 1.76-1.62 (m, 2H). LCMS Method 7—Tr=3.73 min (ES+)(M+H)+ 524.2

Example 95: (4-{2,4-Dimethyl-5-[(1-phenylpyrrolidin-3-yl)amino]benzoyl}-1-phenylpiperazin-2-yl)methanol, I-73

[4-(5-amino-2,4-dimethylbenzoyl)-1-phenylpiperazin-2-yl]methanol[Intermediate 34] (30 mg, 0.09 mmol) and 1-phenylpyrrolidin-3-one (21mg, 0.13 mmol) were suspended in DCM (2 ml) and stirred at rt for 1 hr.Sodium triacetoxyborohydride (45 mg, 0.21 mmol) was added and thereaction was stirred for 16 h. Additional Sodium triacetoxyborohydride(45 mg, 0.21 mmol) and glacial acetic acid (1 ml) was added and thereaction stirred for 16 h. The reaction mixture was partitioned betweenDCM (4 ml) and water (5 ml). The aqueous phase was extracted with DCM (5ml). The organics were combined and concentrated in vacuo. The resultantresidue was purified by preparative HPLC [UV-Directed High pH prepmethod]. The fractions containing product were combined and concentratedin vacuo to yield the title compound I-73 as a white solid (5 mg, 12%).¹H NMR (500 MHz, Chloroform-d) δ 7.31-7.26 (m, 2H), 7.26-7.20 (m, 2H),7.00-6.83 (m, 4H), 6.72 (t, J=7.2 Hz, 1H), 6.60 (s, 1H), 6.58 (s, 1H),6.53 (s, 1H), 4.86-4.74 (m, 1H), 4.31-4.02 (m, 2H), 3.73-3.56 (m, 5H),3.53-2.94 (m, 8H), 2.42-2.32 (m, 1H), 2.30-2.13 (m, 3H), 2.12-2.02 (m,4H). LCMS Method 7—Tr=3.97 min (ES+) (M+H)+485.3

Example 96: 2-(4-{2,4-Dimethyl-5-[(1-phenylazepan-4-yl)amino]benzoyl}piperazin-1-yl)benzonitrile, I-78

The title compound was synthesized from2-[4-(5-amino-2,4-dimethylbenzoyl)piperazin-1-yl]benzonitrile[Intermediate 38] (40 mg, 0.09 mmol) and 1-phenylazepan-4-one[Intermediate 39] (27 mg, 0.14 mmol) using the method described abovefor example 95 to afford the title compound I-78 as a white solid (6 mg,12%). ¹H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J=7.5 Hz, 1H), 7.51 (s,1H), 7.25-7.16 (m, 2H), 7.07 (t, J=7.5 Hz, 1H), 7.01 (d, J=7.9 Hz, 1H),6.86 (s, 1H), 6.71 (d, J=8.2 Hz, 2H), 6.66 (s, 1H), 6.34 (s, 1H), 4.03(s, 2H), 3.66-3.53 (m, 2H), 3.51-3.45 (m, 4H), 3.44-3.29 (m, 1H),3.27-3.20 (m, 2H), 3.07 (s, 2H), 2.19 (s, 1H), 2.17 (s, 3H), 1.99-1.57(m, 9H). LCMS Method 7—Tr=4.32 min (ES+) (M+H)+ 508.4

Example 97:2-[4-(5-{[1-(4-cyanophenyl)azepan-4-yl]amino}-2,4-dimethylbenzoyl)piperazin-1-yl]benzonitrile, I-80

The title compound was synthesized from2-[4-(5-amino-2,4-dimethylbenzoyl)piperazin-1-yl]benzonitrile[Intermediate 38] (40 mg, 0.09 mmol) and 1-phenylazepan-4-one[Intermediate 46] (27 mg, 0.14 mmol) using the method described abovefor example 95 to afford the title compound I-80 as a white solid (16mg, 32%). ¹H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J=7.3 Hz, 1H), 7.52(s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.07 (t, J=7.5 Hz, 1H), 7.01 (d, J=8.3Hz, 1H), 6.88 (s, 1H), 6.68 (s, 2H), 6.33 (s, 1H), 4.02 (d, J=38.6 Hz,2H), 3.70-3.32 (m, 8H), 3.30-3.19 (m, 2H), 3.12-3.04 (m, 2H), 2.28-2.20(m, 1H), 2.18 (s, 3H), 2.04-1.91 (m, 5H), 1.89-1.75 (m, 2H), 1.68-1.60(m, 1H). LCMS Method 7—Tr=4.05 min (ES+) (M+H)+ 533.4

Example 98:2-[4-(5-{[1-(3-cyanophenyl)azepan-4-yl]amino}-2,4-dimethylbenzoyl)piperazin-1-yl]benzonitrile, I-81

The title compound was synthesized from2-[4-(5-amino-2,4-dimethylbenzoyl)piperazin-1-yl]benzonitrile[Intermediate 38] (40 mg, 0.09 mmol) and 1-phenylazepan-4-one[Intermediate 45] (27 mg, 0.14 mmol) using the method described abovefor example 95 to afford the title compound I-81 as a white solid (4 mg,8%). ¹H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J=7.7 Hz, 1H), 7.52 (t,J=7.7 Hz, 1H), 7.28 (s, 1H), 7.25 (s, 1H), 7.07 (t, J=7.5 Hz, 1H), 7.01(s, 1H), 6.94-6.84 (m, 4H), 6.34 (s, 1H), 4.12-3.94 (m, 2H), 3.65-3.16(m, 11H), 3.12-3.04 (m, 2H), 2.27-2.20 (m, 1H), 2.18 (s, 3H), 1.99-1.94(m, 4H), 1.88-1.77 (m, 2H). LCMS Method 7—Tr=4.20 min (ES+) (M+H)+ 533.4

Example 99: 2-[4-({3-[(3R orS)-3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-4-methylphenyl}amino)piperidin-1-yl]benzonitrile, I-82 Example 100:2-[4-({3-[(3S orR)-3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-4-methylphenyl}amino)piperidin-1-yl]benzonitrile, I-83

2-[4-({3-[3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-4-methylphenyl}amino)piperidin-1-yl]benzonitrile[Example 58] was dissolved to 38.75 mg/mL in methanol and was thenpurified by SFC. Combined fractions of the first eluting peak 1 at1-682.22 min and the second eluting peak 2 at 2.93 min were thenevaporated to near dryness using a rotary evaporator, transferred intofinal vessels with DCM, which was removed under a stream of nitrogen at40° C. before being stored in a vacuum oven at 40° C. and 5 mbar for 16h to afford the products as white solids. Analysis was performed fromconcentrated fractions prior to final vessel transfer.

Separation Conditions:

-   -   Column Details: CHIRALPAK® AS-H (20 mm×250 mm, 5 um)    -   Column Temperature: 40° C.    -   Flow Rate: 50 mL/min    -   BPR: 125 BarG    -   Detector Wavelength: 210 nm    -   Injection Volume: 400 uL (15.5 mg)    -   Isocratic Conditions: 40:60 MeOH:CO₂ (0.1% v/v NH₃)        The Stereochemistry was Arbitrarily Assigned:

Peak 1—2-[4-({3-[(3R orS)-3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-4-methylphenyl}amino)piperidin-1-yl]benzonitrile

HPLC Method A—Tr=2.594 mins

Peak 2—2-[4-({3-[(3S orR)-3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-4-methylphenyl}amino)piperidin-1-yl]benzonitrile

HPLC Method A—Tr=2.596 mins

Example 101: 2-[4-({5-[(3R orS)-3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2-methylphenyl}amino)piperidin-1-yl]benzonitrile,I-84 Example 102: 2-[4-({5-[(3S orR)-3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2-methylphenyl}amino)piperidin-1-yl]benzonitrile,I-85

2-[4-({5-[3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2-methylphenyl}amino)piperidin-1-yl]benzonitrile[Example 56] was dissolved to 10.3 mg/mL in methanol:DCM (3:1) and wasthen purified by SFC. Combined fractions of the first eluting peak 1 at2.87 min and the second eluting peak 2 at 3.63 min were then evaporatedto near dryness using a rotary evaporator, transferred into finalvessels with DCM, which was removed under a stream of nitrogen at 40° C.before being stored in a vacuum oven at 40° C. and 5 mbar for 16 h toafford the products as a white solid. Analysis was performed fromconcentrated fractions prior to final vessel transfer.

Separation Conditions:

-   -   Column Details: CHIRALPAK® AS-H (20 mm×250 mm, 5 um)    -   Column Temperature: 40° C.    -   Flow Rate: 50 mL/min    -   BPR: 125 BarG    -   Detector Wavelength: 210 nm    -   Injection Volume: 1500 uL (15.5 mg)    -   Isocratic Conditions: 40:60 MeOH:CO₂ (0.1% v/v NH₃)        The Stereochemistry was Arbitrarily Assigned:

Peak 1—2-[4-({5-[(3R orS)-3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2-methylphenyl}amino)piperidin-1-yl]benzonitrile

HPLC Method A—Tr=2.864 mins

Peak 2—2-[4-({5-[(3S orR)-3-(hydroxymethyl)-4-phenylpiperazine-1-carbonyl]-2-methylphenyl}amino)piperidin-1-yl]benzonitrile

HPLC Method A—Tr=2.865 mins

Example 103: 2-[4-({5-[(3R or3S)-4-(2-Cyanophenyl)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-133 Example 104: 2-[4-({5-[(3S or3R)-4-(2-cyanophenyl)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-134

2-[4-(5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoyl)-2-(hydroxymethyl)piperazin-1-yl]-N-methylbenzamide[Example 60] (11 mg, 0.019 mmol) was dissolved to 35 mg/mL in methanoland was then purified by SFC. The first eluting peak and second elutingpeak fractions were then evaporated to near dryness using a rotaryevaporator, transferred into final vessels with DCM, which was removedunder a stream of nitrogen at 40° C. before being stored in a vacuumoven at 40° C. and 5 mbar for 16 h. Peak 1 afford [Example103]2-[4-({5-[(3R or 3S)-4-(2-Cyanophenyl)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrileas a solid (3.9 mg). ¹H NMR (500 MHz, Chloroform-d) δ 8.87-8.32 (m, 1H),7.99 (s, 0.3H), 7.97-7.82 (m, 1H), 7.57 (dd, J=7.7, 1.3 Hz, 1H),7.52-7.37 (m, 2H), 7.11-6.97 (m, 2H), 6.97-6.82 (m, 1H), 6.65-6.38 (m,1H), 4.77-4.37 (m, 1H), 3.75-3.41 (m, 7H), 3.41-3.25 (s, 2H), 3.23-3.08(m, 1H), 3.08-2.81 (m, 7H), 2.80-2.68 (m, 1H), 2.30-2.08 (m, 9H),1.83-1.74 (s, 2H).

Chiral LCMS (35% IPA: 65% CO₂ with CHIRALPAK® AS-H 25 cm column at 4ml/min) Tr=7.15 min chiral purity 98% ee

And peak 2 [Example 104]—2-[4-({5-[(3S or3R)-4-(2-cyanophenyl)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrileas solid (5.9 mg) ¹H NMR (500 MHz, Chloroform-d) δ 8.92-8.43 (m, 1H),8.00 (s, 1H), 7.97-7.85 (m, 1H), 7.61-7.53 (m, 1H), 7.52-7.42 (m, 2H),7.25-7.23 (m, 1H), 7.06-6.99 (m, 2H), 6.95-6.90 (m, 1H), 6.65-6.37 (m,1H), 4.66-4.34 (m, 1H), 3.76-3.40 (m, 7H), 3.40-3.26 (m, 2H), 3.13 (s,1H), 3.07-2.91 (m, 7H), 2.78-2.72 (m, 1H), 2.38-2.09 (m, 9H), 1.82-1.64(m, 2H). Chiral LCMS (Lux A1 (4.6 mm×250 mm, 5 um)-35% IPA: 65% CO₂ withCHIRALPAK® AS-H 25 cm column at 4 ml/min) Tr=11.60 min chiral purity100% ee

Separation Conditions:

-   -   Column Details: CHIRALPAK® AS-H 25 cm column    -   Flow Rate: 15 ml/min    -   Isocratic Conditions: 30% IPA: 70% CO₂    -   The stereochemistry was arbitrarily assigned

Example 105: 2-[4-({5-[(3R or3S)-4-(2-Cyanophenyl)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-77 Example 106: 2-[4-({5-[(3S or3R)-4-(2-Cyanophenyl)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-79

The racemic material was synthesized from tert-Butyl4-(2-cyanophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate[Intermediate 59] (60 mg, 0.17 mmol) the compound was treated with 4MHCl in dioxane (2 ml) for 2 h. The reaction mixture was reduced toafford 5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoicacid.

5-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid fromabove and 5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoicacid [Intermediate 1] (27 mg, 0.14 mmol) coupled together using themethod described above for example 1 to afford the racemic material (59mg, 62%).

The racemic material was dissolved to 35 mg/mL in methanol and was thenpurified by SFC. The first eluting peak and second eluting peakfractions were then evaporated to near dryness using a rotaryevaporator, transferred into final vessels with DCM, which was removedunder a stream of nitrogen at 40° C. before being stored in a vacuumoven at 40° C. and 5 mbar for 16 h. Peak 1 afforded 2-[4-({5-[(3R or3S)-4-(2-Cyanophenyl)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrileI-77 (15.1 mg)

¹H NMR—(500 MHz, Chloroform-d) δ 7.63-7.54 (m, 2H), 7.54-7.29 (m, 3H),7.18-6.96 (m, 4H), 6.96-6.82 (m, 1H), 6.61-6.41 (m, 1H), 4.72-4.54 (s,0.7H), 4.47-4.26 (m, 0.3H), 4.08-3.94 (m, 0.7H), 3.85-3.75 (m, 0.7H),3.70-3.41 (m, 9H), 3.38-3.32 (m, 0.7H), 3.23-3.14 (m, 0.4H), 3.07-2.93(m, 2.6H), 2.90-2.72 (m, 0.6H), 2.30-2.16 (m, 5H), 1.81-1.67 (m, 2.4H),1.42-1.23 (m, 2H).

Chiral LCMS (35% IPA: 65% CO₂ with CHIRALPAK® AS-H 25 cm column at 4ml/min) Tr=3.69 min chiral purity 100% ee

And peak 2 afforded 2-[4-({5-[(3R or3S)-4-(2-Cyanophenyl)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrileI-79 (16.3 mg)

¹H NMR—(500 MHz, Chloroform-d) δ 7.62-7.54 (m, 2H), 7.53-7.28 (m, 3H),7.18-6.99 (m, 4H), 6.97-6.90 (m, 1H), 6.61-6.41 (m, 1H), 4.71-4.55 (m,0.7H), 4.47-4.27 (m, 0.3H), 4.09-3.93 (m, 0.7H), 3.85-3.75 (m, 0.7H),3.70-3.41 (m, 9H), 3.38-3.32 (m, 0.7H), 3.23-3.14 (m, 0.4H), 3.07-2.93(m, 2.6H), 2.90-2.72 (m, 0.6H), 2.31-2.17 (m, 5H), 1.86-1.67 (m, 2.4H),1.41-1.26 (m, 2H).

Chiral LCMS (Lux A1 (4.6 mm×250 mm, 5 um)-35% IPA: 65% CO₂ withCHIRALPAK® AS-H 25 cm column at 4 ml/min) Tr=5.53 min chiral purity 99%ee

Separation Conditions:

-   -   Column Details: CHIRALPAK® AS-H 25 cm column    -   Flow Rate: 15 ml/min    -   Isocratic Conditions: 30% IPA: 70% CO₂

The Stereochemistry was Arbitrarily Assigned

Example 107: 2-[4-({5-[(3R or3S)-3-(hydroxymethyl)-4-(pyridin-2-yl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-48 Example 108: 2-[4-({5-[(3S or3R)-3-(hydroxymethyl)-4-(pyridin-2-yl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-38

2-[4-({5-[3-(hydroxymethyl)-4-(pyridin-2-yl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrilewas dissolved to 8 mg/mL in methanol and was then purified by HPLC.Combined fractions of each of first eluting peak at 5.53 mins and secondeluting peak at 7.01 min were then evaporated to near dryness using arotary evaporator, transferred into final vessels with DCM, which wasremoved under a stream of nitrogen at 40° C. before being stored in avacuum oven at 40° C. and 5 mbar for 16 h to afford peak 1 I-48 and peak2 I-38 as white solids. Analysis of 1-48 and 1-38 were performed withconcentrated fractions prior to final vessel transfer.

Separation Conditions:

-   -   Column Details: Lux C₁ (21.2 mm×250 mm, 5 um)    -   Column Temperature: Ambient    -   Flow Rate: 21 mL/min    -   Detector Wavelength: 220 nm    -   Injection Volume: 1500 uL (12 mg)    -   Isocratic Conditions: MeOH (0.1% v/v NH₃)        The Stereochemistry was Arbitrarily Assigned:

2-[4-({5-[(3R or3S)-3-(hydroxymethyl)-4-(pyridin-2-yl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile(4.3 mg)

Peak 1 at 5.53 min

¹H NMR (500 MHz, Chloroform-d) δ 8.20-8.03 (m, 1H), 7.61-7.42 (m, 3H),7.09-6.97 (m, 2H), 6.97-6.82 (m, 1H), 6.75-6.59 (m, 2H), 6.59-6.28 (m,1H), 4.86-4.21 (m, 2H), 4.07-2.71 (m, 14H), 2.30-2.09 (m, 8H), 1.78-1.67(m, 2H). 2-[4-({5-[(3S or3R)-3-(hydroxymethyl)-4-(pyridin-2-yl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile(3.0 mg)

Peak 2 at 7.01 min

¹H NMR (500 MHz, Chloroform-d) δ 8.20-8.04 (m, 1H), 7.63-7.40 (m, 3H),7.09-6.97 (m, 2H), 6.97-6.85 (m, 1H), 6.74-6.58 (m, 2H), 6.60-6.28 (m,1H), 4.92-4.18 (m, 2H), 3.98-2.93 (m, 14H), 2.29-2.09 (m, 8H), 1.88-1.66(m, 2H).

Example 109:2-[4-(5-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoyl)piperazin-1-yl]-6-fluorobenzene-1-sulfonamide, I-24

tert-Butyl 4-(3-fluoro-2-sulfamoylphenyl)piperazine-1-carboxylate[Intermediate 62] (39.5 mg, 0.11 mmol) was dissolved in 1,4-dioxane (0.6ml) and 4M HCl in 1,4-dioxane and stirred for 2 h. The suspension wascarefully blown down with dry nitrogen to yield2-fluoro-6-(piperazin-1-yl)benzenesulfonamide dihydrochloride as a whitecrystalline solid.

5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid[Intermediate 1] (34.9 mg, 0.1 mmol) and DIPEA (69.7 μl, 0.4 mmol) weredissolved in DCM (0.5 ml) under nitrogen atmosphere. The reactionmixture was cooled 0° C. and a solution of thionyl chloride (8.8 μl,0.12 mmol) in DCM (0.5 ml) was added dropwise to the reaction mixture.The reaction mixture was warmed to rt and stirred for 1 h. The reactionmixture was reduced and redissolved in DCM (1 ml) and the processrepeated. The residue was dissolved in DCM (1 ml) and2-fluoro-6-(piperazin-1-yl)benzenesulfonamide dihydrochloride (0.11mmol) was added and the reaction stirred for 1 h at rt. The reactionmixture was concentrated in vacuo to yield the crude product as a browngum. The crude product was purified by preparative HPLC [GenericUV-Directed low pH prep method] to yield the title compound as a palebeige solid (13.3 mg, 22%). ¹H NMR (500 MHz, Chloroform-d) δ 7.56 (dd,J=7.7, 1.6 Hz, 1H), 7.54-7.45 (m, 2H), 7.10 (d, J=8.1 Hz, 1H), 7.07-6.98(m, 3H), 6.92 (s, 1H), 6.47 (s, 1H), 5.78 (s, 2H), 3.75-2.46 (m, 12H),2.31-2.08 (m, 8H), 1.87-1.58 (m, 4H). LCMS Method 7—Tr=3.50 mins, (ES+)(M+H⁺) 591.

Example 110:2-{2-[4-(5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoyl)piperazin-1-yl]-6-fluorobenzenesulfonyl}-1,1,3,3-tetramethylguanidine,I-19

tert-Butyl 4-(3-fluoro-2-sulfamoylphenyl)piperazine-1-carboxylate[Intermediate 62] (39.5 mg, 0.11 mmol) was dissolved in 1,4-dioxane (0.6ml) and 4M HCl in 1,4-dioxane and stirred for 2 h. The suspension wascarefully blown down with dry nitrogen to yield2-fluoro-6-(piperazin-1-yl)benzenesulfonamide dihydrochloride as a whitecrystalline solid.

5-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid[Intermediate 1] (30 mg, 0.086 mmol) in dry DMF (1.5 ml) under nitrogenwas treated with 2-fluoro-6-(piperazin-1-yl)benzenesulfonamidehydrochloride (36.2 mg, 0.123 mmol) and HATU (56 mg, 0.147 mmol). DIPEA(85 μL, 0.491 mmol),was then added and the reaction mixture stirred atambient temperature overnight. HPLC showed mass for thesulphonyl-guanidine product rather than the expected sulphonamide. Thereaction was reduced in vacuo to yield pale red residual gum. Theresidue was dissolved in DCM and filtered, the filtrate was diluted withMBTE and the supernatant discarded. The resultant precipitate wasdissolved in DCM and purified by flash column chromatography on silicagel (5 g) eluting with a gradient of 0% to 100% acetone in MBTE to yieldthe title compound I-19 as a pale pink solid (28.5 mg, 34%). ¹H NMR (500MHz, Chloroform-d) δ 7.56 (dd, J=7.7, 1.6 Hz, 1H), 7.52-7.45 (m, 1H),7.42-7.28 (m, 1H), 7.05 (d, J=8.2 Hz, 1H), 7.00 (t, J=7.5 Hz, 1H),6.97-6.63 (m, 2H), 6.90 (s, 1H), 6.50 (s, 1H), 3.79-3.14 (m, 8H),3.13-2.49 (m, 4H), 2.95 (s, 12H), 2.34-1.91 (m, 8H), 1.85-1.62 (m, 3H).LCMS Method 6—Tr=4.79 min, (ES+) (M+H⁺) 689

Example 111:2-[4-({5-[4-(5-Fluoropyridin-2-yl)-3-oxopiperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-72

The title compound was synthesized from5-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid[Intermediate 1] (26 mg, 0.075 mmol) and tert-Butyl4-(5-fluoropyridin-2-yl)-3-oxopiperazine-1-carboxylate [Intermediate 63](29 mg, 0.1 mmol) using the method described above for example 109 toafford the title compound I-72 as a beige solid (7.8 mg, 20%). ¹H NMR(500 MHz, Chloroform-d) δ 8.33-8.19 (m, 1H), 8.09-7.91 (m, 1H), 7.56(dd, J=7.6, 1.5 Hz, 1H), 7.52-7.40 (m, 2H), 7.05-6.98 (m, 2H), 6.95 (d,J=7.6 Hz, 1H), 6.62-6.44 (m, 1H), 4.90-4.36 (m, 1H), 4.34-3.89 (m, 4H),3.70-3.41 (m, 4H), 3.02-2.89 (m, 2H), 2.27-2.11 (m, 8H), 1.75 (s, 1H),1.74 (s, 2H). LCMS Method 7—Tr=3.59 mins, (ES+) (M+H⁺) 527.

Example 112:2-[4-({5-[4-(2-Fluorophenyl)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-74

The title compound was synthesized from5-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid[Intermediate 1] and tert-Butyl4-(2-fluorophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate[Intermediate 64] using the method described above for example 109 withthe exception of the compound being purified by [Generic UV-Directedhigh pH prep method] which afford the title compound I-74 as a beigesolid (40 mg, 75%). ¹H NMR VT (250 MHz, DMSO-d6) δ 7.63 (dd, J=7.7, 1.5Hz, 1H), 7.57 (ddd, J=9.0, 7.5, 1.6 Hz, 1H), 7.27-6.93 (m, 6H), 6.88 (s,1H), 6.47 (s, 1H), 4.26 (d, J=7.9 Hz, 2H), 3.80-3.33 (m, 10H), 3.27-3.05(m, 3H), 2.11 (d, J=3.5 Hz, 6H), 2.07 (s, 2H), 1.84-1.60 (m, 2H). LCMSMethod 7—Tr=3.82 mins, (ES+) (M+H⁺) 542

Example 113:2-[4-({5-[4-(3-Fluorophenyl)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-75

The title compound was synthesized from5-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid[Intermediate 1] and tert-Butyl4-(3-fluorophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate[Intermediate 65] using the method described above for example 112 toafford the title compound I-75 as a white solid (45.1 mg, 83%). ¹H NMRVT (250 MHz, DMSO-d6) 7.63 (dd, J=7.7, 1.6 Hz, 1H), 7.56 (ddd, J=9.0,7.4, 1.7 Hz, 1H), 7.27-7.11 (m, 2H), 7.04 (td, J=7.5, 1.0 Hz, 1H), 6.88(s, 1H), 6.77-6.59 (m, 2H), 6.54-6.39 (m, 2H), 4.99-3.05 (m, 16H),2.19-1.94 (m, 8H), 1.82-1.61 (m, 2H). LCMS Method 7—Tr=3.85 mins, (ES+)(M+H⁺) 542.

Example 114:2-[4-({5-[4-(4-fluorophenyl)-3-(hydroxymethyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-76

The title compound was synthesized from5-{[1-(2-Cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid[Intermediate 1] and tert-Butyl4-(4-fluorophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate[Intermediate 66] using the method described above for example 112 toafford the title compound I-76 as a white solid (43.8 mg, 81%). ¹H NMRVT (250 MHz, DMSO-d6) δ 7.69-7.50 (m, 2H), 7.17 (d, J=8.0 Hz, 1H),7.11-6.85 (m, 6H), 6.45 (s, 1H), 4.42-4.19 (m, 2H), 3.89-3.19 (m, l 1H),3.07 (s, 2H), 2.14-2.03 (m, 8H), 1.81-1.62 (m, 2H). LCMS Method7—Tr=3.76 mins (ES+) (M+H⁺) 542.

Example 115:2-[4-({3-[3-(Aminomethyl)-4-phenylpiperazine-1-carbonyl]-2,4,6-trimethylphenyl}amino)piperidin-1-yl]benzonitrile;bis(formic acid) salt, I-135

In a pressure tube, a stirred solution of2-{4-[(3-{3-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-4-phenylpiperazine-1-carbonyl}-2,4,6-trimethylphenyl)amino]piperidin-1-yl}benzonitrile[Intermediate 117] (141 mg, 0.21 mmol) in EtOH (5 ml) was treated withhydrazine hydrate (1:1) (44 μl, 0.9 mmol). The tube was sealed andheated at 90° C. for 3 hours. The reaction mixture was concentrated invacuo. The crude product was purified by preparative HPLC [GenericUV-Directed low pH prep method] to yield the title compound I-135 as ayellow solid (38 mg, 27%). Atropoisomerism observed. ¹H NMR (250 MHz,DMSO-d6) 3 8.26 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H),7.28-7.11 (m, 3H), 7.06 (t, J=7.5 Hz, 1H), 7.01-6.82 (m, 3H), 6.77 (t,J=6.9 Hz, 1H), 4.62-3.89 (m, 3H), 3.38 (s, 3H), 3.18 (s, 3H), 3.05-2.59(m, 6H), 2.25 (s, 3H), 2.21-2.07 (m, 3H), 2.01 (d, J=6.8 Hz, 3H), 1.87(s, 2H), 1.70 (d, J=10.8 Hz, 2H). LCMS Method 5—Tr=2.23, 2.34, 2.45,2.60 min (ES+) (M+H⁺⁾ 537.3

Example 116:2-[4-({3-[(3S)-4-(3,4-Difluorophenyl)-3-(hydroxymethyl)-5-oxopiperazine-1-carbonyl]-2,4,6-trimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-136

To a solution of3-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4,6-trimethylbenzoic acidhydrochloride [Intermediate 111] (50 mg, 0.13 mmol) and HATU (52 mg,0.14 mmol) in DMF (3 ml) was added DiPEA (87 μl, 0.5 mmol). The reactionmixture stirred at ambient temperature for 30 mins.(6S)-1-(3,4-difluorophenyl)-6-(hydroxymethyl)piperazin-2-one (31 mg,0.13 mmol) [Intermediate 128] was added and the reaction mixture washeat at 50° C. overnight. The crude reaction mixture was purified bypreparative HPLC [UV-Directed Low pH prep method]. The fractionscontaining product were combined and concentrated in vacuo to afford thetitle compound I-136 as a white solid (23 mg, 31%). Atropisomerismobserved. ¹H NMR (500 MHz, DMSO-d6) δ 7.71-7.65 (m, 1H), 7.61-7.45 (m,3H), 7.22 (t, J=8.9 Hz, 1H), 7.17-7.10 (m, 1H), 7.10-7.02 (m, 1H),6.95-6.83 (m, 1H), 5.08-4.70 (m, 1H), 4.64-4.38 (m, 1H), 4.21-3.92 (m,1H), 3.91-3.68 (m, 3H), 3.67-3.37 (m, 5H), 2.94 (s, 1H), 2.86-2.70 (m,2H), 2.30-2.21 (m, 3H), 2.19-2.04 (m, 6H), 1.96-1.79 (m, 2H), 1.77-1.60(m, 2H). LCMS Method 5—Tr=3.6, 3.10 min (ES+) (M+H⁺) 589

Example 117:2-[4-({3-[(3R)-3-(Aminomethyl)-4-phenylpiperazine-1-carbonyl]-2,4,6-trimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-137

In a pressure tube, a stirred solution of2-[4-({3-[(3S)-3-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-4-phenylpiperazine-1-carbonyl]-2,4,6-trimethylphenyl}amino)piperidin-1-yl]benzonitrile[Intermediate 115] (90%, 210 mg, 0.28 mmol) in EtOH (8 ml) was treatedwith hydrazine hydrate (1:1) (59 μl, 1.2 mmol). The tube was sealed andstirred at 90° C. for 3 hours. The reaction mixture was concentrated invacuo. The residue was dissolved in EtOAc (20 ml) and washed with 1M aq.NaOH (20 ml). The aqueous phase was extracted with EtOAc (2×20 ml). Thecombined organics were dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was dissolved in the minimum volume of (1:1)MeOH/DCM and loaded onto an SCX-2 cartridge (5 g). The cartridge wassequentially washed with MeOH (10 ml), DCM, (10 ml), MeOH (10 ml), DCM(10 ml) and MeOH (10 ml). The product was eluted with 7M NH₃ in MeOH (30ml). The resulting fractions were concentrated in vacuo to yield thetitle compound I-137 as a cream solid (114 mg, 74%). Atropisomerismobserved. ¹H NMR (500 MHz, DMSO-d6) δ 7.67 (dt, J=7.6, 2.3 Hz, 1H),7.60-7.51 (m, 1H), 7.19 (t, J=7.8 Hz, 2H), 7.16-7.11 (m, 1H), 7.06 (t,J=7.5 Hz, 1H), 6.95-6.82 (m, 3H), 6.72 (q, J=7.0 Hz, 1H), 4.75-3.98 (m,1H), 3.90-3.38 (m, 5H), 3.30-3.02 (m, 4H), 3.01-2.68 (m, 4H), 2.67-2.54(m, 1H), 2.29-2.21 (m, 3H), 2.19-2.08 (m, 3H), 2.07-1.98 (m, 3H),1.96-1.60 (m, 5H), 1.51 (s, 1H). LCMS Method 5—Tr=2.23, 2.35, 2.46, 2.61min (ES+) (M+H⁺) 537.3

Example 118:5-Fluoro-2-[4-[3-[(3S)-3-(hydroxymethyl)-4-pyridazin-3-yl-piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]benzonitrile,I-141

[(2S)-1-pyridazin-3-ylpiperazin-2-yl]MeOH [Intermediate 82] (73 mg, 0.38mmol) and DiPEA (178 μl, 1.02 mmol) were suspended in DCM (1 ml) andMeCN (1.5 ml) with stirring.3-{[1-(2-cyano-4-fluorophenyl)piperidin-4-yl]amino}-2,4,6-trimethylbenzoylchloride hydrochloride [Intermediate 93] (149 mg, 0.34 mmol) wasdissolved in DCM (2.0 ml) then the solution was slowly added to thereaction mixture. The reaction was stirred at ambient temperature for 4hours. The reaction was partitioned between DCM (2 ml) and water (3 ml)then the organics were separated and concentrated in vacuo. The residueobtained was purified via flash column chromatography using a gradientof 0% to 100% EtOAc in heptane followed by a gradient of 0% to 100% MeOHin EtOAc. The fractions containing product were combined andconcentrated in vacuo. The resultant residue was purified by preparativeHPLC [UV-Directed High pH prep method]. The fractions containing productwere combined and reduced in vacuo. The resultant residue purifiedfurther by preparative HPLC [UV-Directed Low pH prep method]. Thefractions containing product were combined and reduced in vacuo to yieldthe title compound I-141 as a white powdery solid (28.9 mg, 15%).Atropisomerism observed. ¹H NMR (500 MHz, DMSO-d6) δ 8.53 (dd, J=7.9,4.4 Hz, 1H), 7.69 (dd, J=8.4, 3.1 Hz, 1H), 7.47 (t, J=8.8 Hz, 1H),7.40-7.34 (m, 1H), 7.19 (dq, J=9.8, 5.8, 5.1 Hz, 2H), 6.90-6.82 (m, 1H),4.80 (d, J=98.3 Hz, 1H), 4.63-4.42 (m, 1H), 4.23 (d, J=13.1 Hz, 2H),3.80-3.65 (m, 1H), 3.57 (s, 1H), 3.50-3.35 (m, 4H), 3.21 (d, J=10.7 Hz,1H), 3.15-3.01 (m, 1H), 2.82 (d, J=43.9 Hz, 3H), 2.46 (s, 1H), 2.23 (d,J=3.8 Hz, 3H), 2.19-2.09 (m, 3H), 1.98 (dd, J=18.1, 12.1 Hz, 3H), 1.86(s, 2H), 1.68 (s, 2H). LCMS Method 4—Tr=3.14, 3.22, 3.25, 3.30 min (ES+)(M+H⁺) 558.2. LCMS Method 5—Tr=2.19, 2.24, 2.28, 2.35 min (ES+) (M+H⁺)558.2.

Example 119:[(3S)-4-(5-Fluoro-2-pyridyl)-3-(hydroxymethyl)piperazin-1-yl]-[3-[[1-(5-fluoro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-phenyl]methanone,I-146

[(2S)-1-(5-fluoro-2-pyridyl)piperazin-2-yl]MeOH (16 mg, 0.08 mmol)[Intermediate 124] and DiPEA (38 μl, 0.22 mmol) were dissolved in DCM (1ml).3-[[1-(5-Fluoro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethylbenzoylchloride hydrochloride [Intermediate 92] (30 mg, 0.07 mmol) was addedand the reaction was stirred at ambient temperature for 18 hours. Thereaction was partitioned between DCM (2 ml) and sat. aq. NaHCO₃(2 ml),the organics were separated and concentrated in vacuo. The resultantresidue was purified via flash column chromatography using a gradient of0% to 100% EtOAc in heptane followed by a gradient of 0% to 100% MeOH inEtOAc. The fractions containing product were combined and concentratedin vacuo to afford the title compound I-146 as a pale yellow glassysolid (18.3 mg, 46%). Atropisomerism observed. ¹H NMR (500 MHz, DMSO-d6)δ 8.08-8.03 (m, 2H), 7.47 (ddt, J=20.7, 8.4, 4.4 Hz, 2H), 6.86 (dd,J=9.3, 3.1 Hz, 1H), 6.80 (td, J=10.1, 9.4, 3.8 Hz, 2H), 4.86-4.53 (m,2H), 4.30 (d, J=28.0 Hz, 1H), 4.18 (d, J=12.5 Hz, 2H), 4.03 (d, J=4.6Hz, 1H), 3.96 (d, J=10.4 Hz, 1H), 3.65-3.55 (m, 1H), 3.50 (d, J=33.5 Hz,1H), 3.46-3.33 (m, 2H), 3.21 (dd, J=29.2, 11.7 Hz, 2H), 2.96 (d, J=9.9Hz, 1H), 2.84-2.71 (m, 2H), 2.19 (d, J=5.3 Hz, 3H), 2.14-2.08 (m, 3H),1.96 (d, J=14.9 Hz, 3H), 1.76 (d, J=12.7 Hz, 2H), 1.43 (d, J=12.1 Hz,2H). LCMS Method 5—Tr=2.58, 2.72, 2.88, 2.96 min (ES+) (M+H⁺) 551.2.

Example 120:[(2S)-4-(3-{[1-(5-Fluoropyridin-2-yl)piperidin-4-yl]amino}-2,4,6-trimethylbenzoyl)-1-(pyridin-2-yl)piperazin-2-yl]methanol,I-147

Prepared analogously to [Example 119] from3-{[1-(5-fluoropyridin-2-yl)piperidin-4-yl]amino}-2,4,6-trimethylbenzoylchloride hydrochloride [Intermediate 92] and[(2S)-1-(pyridin-2-yl)piperazin-2-yl]methanol [Intermediate 122] toyield the title compound I-147 as a white solid (13 mg, 23%).Atropisomerism observed. ¹H NMR (500 MHz, Chloroform-d) δ 8.15-8.08 (m,1H), 8.04 (t, J=2.6 Hz, 1H), 7.51 (td, J=16.0, 8.7 Hz, 1H), 7.25-7.20(m, 1H), 6.92-6.84 (m, 1H), 6.71-6.59 (m, 3H), 4.77 (dd, J=13.6, 7.9 Hz,1H), 4.66 (s, 1H), 4.17 (d, J=9.0 Hz, 2H), 3.95-3.77 (m, 3H), 3.73-3.56(m, 1H), 3.55-3.45 (m, 1H), 3.44-3.34 (m, 2H), 3.30-3.04 (m, 3H), 2.81(q, J=14.1, 13.6 Hz, 2H), 2.29-2.20 (m, 6H), 2.14-2.08 (m, 3H),2.05-1.93 (m, 2H), 1.50-1.36 (m, 2H). LCMS Method 5—Tr=1.69, 1.78, 1.82,1.90 min (ES+) (M+H⁺) 533.

Example 121:[(3S)-4-(5-Fluoro-2-pyridyl)-3-(hydroxymethyl)piperazin-1-yl]-[2,4,6-trimethyl-3-[(1-pyrazin-2-yl-4-piperidyl)amino]phenyl]methanone,I-148

Prepared analogously to [Example 119] from2,4,6-trimethyl-3-{[1-(pyrazin-2-yl)piperidin-4-yl]amino}benzoylchloride hydrochloride [Intermediate 91] (30 mg, 0.08 mmol) and[(2S)-1-(5-fluoro-2-pyridyl)piperazin-2-yl]MeOH (17.63 mg, 0.08 mmol)[Intermediate 124] to yield the title compound I-148 as a pale yellowglassy solid (17.3 mg, 42%). Atropisomerism observed. ¹H NMR (500 MHz,DMSO-d6) δ 8.31 (d, J=7.5 Hz, 1H), 8.06 (dd, J=7.9, 3.4 Hz, 2H), 7.77(dd, J=2.5, 1.4 Hz, 1H), 7.55-7.48 (m, 1H), 6.88-6.78 (m, 2H), 4.87-4.53(m, 2H), 4.33 (d, J=12.6 Hz, 2H), 4.18-3.92 (m, 2H), 3.68-3.46 (m, 2H),3.41 (d, J=38.0 Hz, 2H), 3.26-3.15 (m, 2H), 3.01 (d, J=35.3 Hz, 2H),2.85 (d, J=30.2 Hz, 2H), 2.20 (d, J=5.4 Hz, 3H), 2.15-2.09 (m, 3H), 1.97(d, J=14.7 Hz, 3H), 1.80 (d, J=13.1 Hz, 2H), 1.45 (d, J=11.9 Hz, 2H).LCMS Method 5—Tr=2.26, 2.43, 2.54, 2.64 min (ES+) (M+H⁺) 534.2.

Example 122:[(2S)-1-(5-Fluoropyridin-2-yl)-4-(2,4,6-trimethyl-3-{[1-(pyrimidin-2-yl)piperidin-4-yl]amino}benzoyl)piperazin-2-yl]methanol,I-151

2,4,6-Trimethyl-3-{[1-(pyrimidin-2-yl)piperidin-4-yl]amino}benzoic acid[Intermediate 113] (38 mg, 0.11 mmol) was dissolved in toluene (3 ml)under nitrogen atmosphere. SOCl₂ (33 μl, 0.45 mmol) was added followedby DMF (1 drop). The reaction mixture was heated for at 70° C. for 1hour. The reaction mixture was concentrated and the resultant residuewas azeotroped with DCM (2×) to yield the acid chloride intermediate.The acid chloride intermediate was dissolved in DCM (3 ml). DiPEA (58μl, 0.33 mmol) and [(2S)-1-(5-fluoropyridin-2-yl)piperazin-2-yl]methanol[Intermediate 124] (26 mg, 0.12 mmol) were added and the reactionmixture was stirred under an atmosphere of nitrogen at ambienttemperature overnight. The reaction mixture was partitioned between sat.aq. NaHCO₃ (5 ml) and DCM. The aqueous phase was extracted with DCM (2×3ml). The organics were combined and concentrated to yield the crudeproduct. The crude product was purified by preparative HPLC [UV-DirectedHigh pH prep method].The product containing fractions were combined andreduced in vacuo to yield the title compound I-151 as a brown solid (5mg, 7% yield). Atropisomerism observed. ¹H NMR (250 MHz, Chloroform-d) δ8.38-8.20 (m, 2H), 8.00 (t, J=3.4 Hz, 1H), 7.36-7.20 (m, 1H), 6.88 (d,J=6.9 Hz, 1H), 6.73-6.54 (m, 1H), 6.47 (t, J=4.7 Hz, 1H), 4.78 (t,J=10.6 Hz, 3H), 4.64-4.41 (m, 1H), 4.40-4.18 (m, 1H), 4.01-3.71 (m, 3H),3.64-3.36 (m, 3H), 3.29-3.04 (m, 3H), 2.96-2.79 (m, 2H), 2.29-2.21 (m,6H), 2.14-2.08 (m, 3H), 2.04-1.95 (m, 2H), 1.46-1.30 (m, 2H). LCMSMethod 5—Tr=2.30, 2.46, 2.60, 2.69 min (ES+) (M+H⁺) 534.

Example 123:(2S)-1-Phenyl-4-(2,4,6-trimethyl-3-{[1-(pyridazin-3-yl)piperidin-4-yl]amino}benzoyl)piperazine-2-carboxamide,I-164

Prepared analogously to [Example 119]2,4,6-trimethyl-3-{[1-(pyridazin-3-yl)piperidin-4-yl]amino}benzoylchloride hydrochloride [Intermediate 105] (50 mg, 0.126 mmol) and(2S)-1-Phenylpiperazine-2-carboxamide [Intermediate 73] (27 mg, 0.129mmol) to yield the title compound I-164 as a white solid (23 mg, 33%).Atropisomerism observed. ¹H NMR (500 MHz, DMSO-d6) δ 8.53-8.45 (m, 1H),7.59-7.41 (m, 1H), 7.37-7.29 (m, 1H), 7.28-7.11 (m, 4H), 6.86-6.69 (m,4H), 4.80-3.90 (m, 4H), 3.76-3.35 (m, 5H), 3.28-2.80 (m, 4H), 2.25-2.18(m, 3H), 2.08-1.99 (m, 6H), 1.88-1.75 (m, 2H), 1.52-1.38 (m, 2H). LCMSMethod 5—Tr=1.55, 1.75, 1.85, 1.94 min (ES+) (M+H⁺) 528.3.

Example 124:[(3S)-3-(Hydroxymethyl)-4-phenyl-piperazin-1-yl]-[2,4,6-trimethyl-3-[(1-pyrimidin-4-yl-4-piperidyl)amino]phenyl]methanone,I-166

[(3S)-3-(hydroxymethyl)-4-phenyl-piperazin-1-yl]-[2,4,6-trimethyl-3-(4-piperidylamino)phenyl]methanone[Intermediate 109] (25 mg, 0.06 mmol), 4-chloropyrimidine hydrochloride(10 mg, 0.07 mmol) and Cs₂CO₃ (19 mg, 0.06 mmol) were suspended intoluene (0.5 ml) in a pressure tube. The reaction was sealed and heatedat 100° C. for 16 hours. The reaction mixture was concentrated in vacuo,and the resulting oil was partitioned between water (1 ml) and EtOAc (1ml). The organic layer was separated, washed with brine (1 ml), driedover Na₂SO₄ and concentrated in vacuo to yield the crude product as anoil. The crude product was purified via preparative HPLC [UV-directedHigh pH prep method]. The product containing fractions were combined andconcentrated in vacuo to give the title compound I-166 as a white solid(6 mg, 20%). Atropisomerism observed. ¹H NMR (500 MHz, Chloroform-d) δ8.60-8.57 (m, 1H), 8.21-8.15 (m, 1H), 7.32-7.27 (m, 2H), 6.99-6.85 (m,4H), 6.54-6.49 (m, 1H), 4.78-3.99 (m, 4H), 3.78-3.55 (m, 3H), 3.54-3.35(m, 3H), 3.32-3.22 (m, 2H), 3.21-3.02 (m, 2H), 2.93-2.81 (m, 2H),2.29-2.22 (m, 6H), 2.15 (s, 3H), 2.03 (d, J=24.4 Hz, 2H), 1.37 (s, 2H).LCMS Method 5—Tr 1.71, 1.94, 1.9, 2.06 min (ES⁺) (M+H⁺) 515.

Example 125: Synthesis of3-(4-(3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4,6trimethylbenzoyl)piperazin-1-yl)pyrazine-2-sulfonamide, I-167

Synthetic Scheme:

Procedures and Characterization:

Step 1:2-[4-[(5-bromo-2,6-dimethyl-3-pyridyl)methyl]-1-piperidyl]benzonitrile

To a solution of 3,5-dibromo-2,6-dimethyl-pyridine (2.40 g, 9.06 mmol),2-(4-amino-1-piperidyl)benzonitrile (1.22 g, 6.04 mmol), C₄H₉ONa (1.16g, 12.08 mmol), and Binap (752.07 mg, 1.21 mmol) in toluene (60 mL) wasadded Pd₂(dba)₃ (553.01 mg, 603.91 umol) under N₂(g), and the mixturewas stirred at 85° C. for 18 h. The mixture was filtrated, concentratedand purified by flash column with eluting with PE:EA from 95:5 to 60:40to get2-[4-[(5-bromo-2,6-dimethyl-3-pyridyl)methyl]-1-piperidyl]benzonitrile(1.50 g, 3.90 mmol, 65% yield) as light yellow solid. MS (EI⁺, m/z):385.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.58 (dd, J=7.7, 1.4 Hz, 1H),7.52-7.46 (m, 1H), 7.07-6.99 (m, 3H), 3.58 (d, J=12.6 Hz, 2H), 3.39 (t,J=8.4 Hz, 1H), 3.05-2.96 (m, 2H), 2.52 (s, 3H), 2.33 (s, 3H), 2.23 (d,J=11.9 Hz, 2H), 1.75 (d, J=10.7 Hz, 2H).

Step 2:2-[4-[(2,6-dimethyl-5-vinyl-3-pyridyl)amino]-1-piperidyl]benzonitrile

A mixture of2-[4-[(5-bromo-2,6-dimethyl-3-pyridyl)amino]-1-piperidyl]benzonitrile(1.48 g, 3.84 mmol),Potassium vinyltrifluoroborate (771.55 mg, 5.76mmol), K₂CO₃(1.06 g, 7.68 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (280.97 mg, 384 umol) in H₂O (22 mL) and1,4-dioxane (90 mL) was stirred at 80° C. for 17 h under N₂(g). Themixture was filtered, the filtrate was washed with water and extractedwith EtOAc (50 mL*2). The org. layer was dried by Na₂SO₄, concentratedand purified by SGC to give2-[4-[(2,6-dimethyl-5-vinyl-3-pyridyl)amino]-1-piperidyl]benzonitrile(1.10 g, 3.31 mmol, 86% yield) as yellow liquid. MS (EI⁺, m/z):333.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.57 (dd, J=7.7, 1.5 Hz, 1H),7.53-7.41 (m, 1H), 7.12-6.93 (m, 3H), 6.88 (dd, J=17.4, 10.9 Hz, 1H),5.59 (dd, J=17.4, 1.0 Hz, 1H), 5.32 (dd, J=11.0, 1.0 Hz, 1H), 3.55 (dd,J=31.9, 8.4 Hz, 3H), 3.10-2.93 (m, 2H), 2.45 (s, 3H), 2.38 (s, 3H), 2.25(d, J=11.7 Hz, 2H), 1.84-1.71 (m, 2H).

Step 3:2-[4-[(5-formyl-2,6-dimethyl-3-pyridyl)amino]-1-piperidyl]benzonitrile

A mixture of2-[4-[(2,6-dimethyl-5-vinyl-3-pyridyl)amino]-1-piperidyl]benzonitrile(1.07 g, 3.22 mmol), Potassium osmate(VI) dihydrate (59.22 mg, 161umol), N-methyl morpholine-n-oxide (1.13 g, 9.66 mmol) in Acetone (25mL) was added Sodium periodate (1.38 g, 6.44 mmol) in H₂O (25 mL),andthe mixture was stirred at 30° C. for 17 h. LC-MS showed the desiredproduct. The mixture was filtered with celite, concentrated and purifiedby flash column eluting with DCM/CH₃OH from 99:1 to 9:1 to get product2-[4-[(5-formyl-2,6-dimethyl-3-pyridyl)amino]-1-piperidyl]benzonitrile(650 mg, 1.94 mmol, 60% yield) as yellow solid. MS (ESI⁺, m/z): 335.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 10.27 (s, 1H), 7.51 (dd, J=7.6, 1.5Hz, 1H), 7.43 (dt, J=15.9, 4.4 Hz, 1H), 7.21 (s, 1H), 6.97 (dd, J=15.2,7.9 Hz, 2H), 3.58-3.37 (m, 3H), 2.94 (t, J=10.7 Hz, 2H), 2.68 (s, 3H),2.38 (s, 3H), 2.18 (d, J=12.4 Hz, 2H), 1.69 (td, J=13.4, 3.6 Hz, 2H).

Step 4:5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,6-dimethyl-pyridine-3-carboxylicacid

To a solution of2-[4-[(5-formyl-2,6-dimethyl-3-pyridyl)amino]-1-piperidyl]benzonitrile(200 mg, 598.07 umol) in BuOH (20 mL) and H₂O (10 mL) was added NaH₂PO₄(358.78 mg, 2.99 mmol), NaClO₂ (108.18 mg, 1.20 mmol),2,3-dimethylbut-2-ene (402.67 mg, 4.78 mmol).the mixture was stirred atroom temperature for 3 h. After reaction, H₂O (30 mL) and EtOAc(30 mL)was added and separated the organic phase, then the aqueous was furtherextracted with EtOAc (2*30 mL) and combine the organic phase, washedwith brine(30 mL),dried with anhydrous Na₂SO₄,filtered and purified byflash column to get5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,6-dimethyl-pyridine-3-carboxylicacid (28 mg, 79.91 umol, 13% yield).MS (EI⁺, m/z): 351.0 [M+H]⁺. ¹H NMR(500 MHz, MeOD-d₄) δ 7.63 (s, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.47 (t,J=7.9 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.97 (t, J=7.5 Hz, 1H), 3.50 (d,J=10.2 Hz, 3H), 2.92 (t, J=11.6 Hz, 2H), 2.58 (s, 3H), 2.40 (s, 3H),2.09 (d, J=14.2 Hz, 2H), 1.74 (d, J=8.9 Hz, 2H).

Step 5:(S)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)-4-(pyridin-2-yl)piperazine-1-carbonyl)-2,6-dimethylpyridin-3-ylamino)piperidin-1-yl)benzonitrile

At r.t, a solution of5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,6-dimethyl-pyridine-3-carboxylicacid (48 mg, 136.98 umol), HOBT (27.76 mg, 205.47 umol), EDCI (39.39 mg,205.47 umol), DIPEA (44.26 mg, 342.45 umol, 59.81 uL) in DMF (5 mL) wasstirred for 1 h, then addedtert-butyl-dimethyl-[[(2S)-1-(2-pyridyl)piperazin-2-yl]methoxy] silane(42.12 mg, 136.98 umol) and continued to stir for 20 h. LC-MS showedwell. the mixture was added water (20 mL) and extracted with EtOAc (30mL*2),combined organic phase and concentrated to get(S)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)-4-(pyridin-2-yl)piperazine-1-carbonyl)-2,6dimethylpyridin-3-ylamino)piperidin-1-yl)benzonitrile (80 mg, 125.02umol, 91% yield). MS (EI⁺, m/z): 640.3 [M+H]⁺.

Step 6:(S)-2-(4-(5-(3-(hydroxymethyl)-4-(pyridin-2-yl)piperazine-1-carbonyl)-2,6-dimethylpyridin-3-ylamino)piperidin-1-yl)benzonitrile

To a solution of(S)-2-(4-(5-(3-((tert-butyldimethylsilyloxy)methyl)-4-(pyridin-2-yl)piperazine-1-carbonyl)-2,6-dimethylpyridin-3-ylamino)piperidin-1-yl)benzonitrile(80 mg, 125.02 umol) was added Triethylamine trihydrofluoride (80.62 mg,500.08 umol) and stirred for 18 h at r.t. LC-MS showed it worked well,the was purified via preparative HPLC to get(S)-2-(4-(5-(3-(hydroxymethyl)-4-(pyridin-2-yl)piperazine-1-carbonyl)-2,6-dimethylpyridin-3-ylamino)piperidin-1-yl)benzonitrile(24 mg, 45.66 umol, 36.52% yield). MS (EI⁺, m/z): 526.3 [M+H]⁺. ¹H NMR(500 MHz, MeOD-d₄) δ 7.99 (s, 1H), 7.56-7.37 (m, 3H), 7.08 (d, J=8.3 Hz,1H), 6.95 (t, J=7.5 Hz, 1H), 6.86 (d, J=39.8 Hz, 1H), 6.72 (t, J=9.4 Hz,1H), 6.57 (dd, J=6.9, 5.1 Hz, 1H), 4.40 (dd, J=142.3, 72.3 Hz, 2H), 3.97(d, J=6.6 Hz, 1H), 3.68 (d, J=12.8 Hz, 1H), 3.61-3.22 (m, 8H), 2.90 (t,J=10.7 Hz, 2H), 2.27 (t, J=24.5 Hz, 6H), 2.11-1.99 (m, 2H), 1.70 (d,J=11.3 Hz, 2H)

Example 126: Synthesis of(S)-2-(4-(3-(3-(hydroxymethyl)-4-(3,4,5-trifluorophenyl)piperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)benzonitrile,I-168

Synthetic Scheme:

Procedures and Characterization:

Step 1: benzyl(3S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazine-1-carboxylate

A mixture of benzyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (1 g,4 mmol), TBSCl (658.04 mg, 7.99 mmol), DMAP (97.62 mg, 799.07 umol), andTEA (2.77 g, 19.98 mmol, 3.82 uL, 73% purity) in DCM (10 mL) was stirredat 25° C. for 2 h. The mixture was washed with 2N NaOH(aq) (40 mL*2) andwater(30 mL), dried with Na₂SO₄,concentrated and purified by SGC to getbenzyl(3S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazine-1-carboxylate(376 mg, 1.03 mmol, 26% yield). MS (EI⁺, m/z): 365.4 [M+H]⁺.

Step 2: benzyl(3S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(3,4,5-trifluorophenyl)piperazine-1-carboxylate

To a solution of 5-bromo-1,2,3-trifluoro-benzene (240 mg, 1.14mmol),benzyl(3S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazine-1-carboxylate(377.81 mg, 1.04 mmol),Sodium tert-butoxide (199.19 mg, 2.07 mmol) intoluene (8 mL) was added Pd[(tBu)3P]2 (79.44 mg, 155.45 umol) underN₂(g), then the mixture was stirred at 80° C. for 18 h. The mixture wasfiltered with celite, concentrated and purified by SGC (PE:EA=7:3) toget benzyl(3S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(3,4,5-trifluorophenyl)piperazine-1-carboxylate(260 mg, 525.66 umol, 51% yield). MS (EI⁺, m/z): 495.3 [M+H]⁺.

Step 3:(S)-2-((tert-butyldimethylsilyloxy)methyl)-1-(3,4,5-trifluorophenyl)piperazine

To a mixture of benzyl3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(3,4,5-trifluorophenyl)piperazine-1-carboxylate(230 mg, 465 umol) in EtOH (10 mL) was added Pd/C (14.85 mg, 139.50umol), and the mixture was kept stirring at 32° C. for 2h under H₂atmosphere. LC-MS showed well, the crude was filtered and purified bySGC to get(S)-2-((tert-butyldimethylsilyloxy)methyl)-1-(3,4,5-trifluorophenyl)piperazine(20 mg, 55.48 umol, 12% yield). MS (ESI⁺, m/z): 361.3 [M+H]⁺.

Step 4: (S)-(1-(3,4,5-trifluorophenyl)piperazin-2-yl)methanol

To a solution of(S)-2-((tert-butyldimethylsilyloxy)methyl)-1-(3,4,5-trifluorophenyl)piperazine(100 mg, 277.40 umol) in THF (2 mL) was added 3TEA-HF (223.60 mg, 1.39mmol) and kept stirred at 25° C. for 2 h. LC-MS showed the desiredproduct, adjusted the pH about 8 and used to the next step withoutfurther purification. MS (EI⁺, m/z): 247.3 [M+H]⁺.

Step 5: 2-[4-[3-[(3S)-3-(hydroxymethyl)-4-(3,4,5trifluorophenyl)piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]benzonitrile

The mixture of3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoic acid(100.37 mg, 276.16 umol), EDCI (52.94 mg, 276.16 umol), HOBt (93.29 mg,690.40 umol). DMAP (3.37 mg, 27.62 umol) and DIPEA (178.46 mg, 1.38mmol, 240.51 uL) in DMF (3 mL) was stirred for 1 h, then added[(2S)-1-(3,4,5-trifluorophenyl)piperazin-2-yl]methanol (68 mg, 276.16umol) and kept stirring overnight. the crude was purified viapreparative HPLC to get 2-[4-[3-[(3 S)-3-(hydroxymethyl)-4-(3,4,5trifluorophenyl)piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]benzonitrile(20 mg, 33.80 umol, 12% yield) as a white solid. MS (EI⁺, m/z): 592.1[M+H]⁺. ¹H NMR (400 MHz, MeOD-d₄) δ 7.61 (d, J=7.7 Hz, 1H), 7.56 (t,J=8.0 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.96 (t,J=7.7 Hz, 1H), 6.70 (d, J=11.3 Hz, 2H), 4.84-4.66 (m, 2H), 3.57 (dt,J=67.9, 45.7 Hz, 8H), 3.12 (d, J=28.8 Hz, 3H), 2.85 (s, 2H), 2.38-2.09(m, 9H), 2.00 (s, 2H), 1.76 (s, 2H).

Example 127:2-(4-(5-(((3R,4S)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-169

Synthetic Scheme:

Procedures and Characterization:

Step 1: tert-butyl 4-amino-3-methylpiperidine-1-carboxylate

To a solution of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (10g, 46.89 mmol) ammonium formate (17.74 g, 281.34 mmol) and molecularsieves (2 g) in MeOH (100 mL) was added NaCNBH₃ (3.54 g, 56.27 mmol).The mixture was stirred at 30° C. for 16 hour. It was purified by SGC toafford tert-butyl 4-amino-3-methyl-piperidine-1-carboxylate (8.12 g,37.89 mmol, 80%) as product. ESI-MS (EI⁺, m/z): 159.3 [M−56+H]⁺.

Step 2: 3-methylpiperidin-4-amine Hydrochloride Salt

tert-butyl 4-amino-3-methyl-piperidine-1-carboxylate (12.18 g, 56.83mmol) was dissolved in HCl (4M, dioxane) (60 mL). It was stirred at 30°C. for 3 hour, concentrated to afford 3-methylpiperidin-4-amine (11.04g, 58.98 mmol, 100%, 2HCl) as a white solid. ESI-MS (EI⁺, m/z): 115.2[M+H]⁺.

Step 3: 2-(4-amino-3-methylpiperidin-1-yl)benzonitrile

To a solution of 2-fluorobenzonitrile (10.65 g, 87.92 mmol) and3-methylpiperidin-4-amine (10.04 g, 87.92 mmol) in DMF (100 mL) wasadded Potassium carbonate (46.18 g, 334.10 mmol), it was stirred at 120°C. for 16 hour. It was diluted with water and extracted with DCM, theorganic layer was washed with water, dried over anhydrous Na₂SO₄,concentrated and purified by SGC to afford2-(4-amino-3-methyl-1-piperidyl)benzonitrile (4.80 g, 22.30 mmol, 25%)as a yellow oil. ESI-MS (EI⁺, m/z): 216.3 [M+H]⁺.

Step 4: methyl5-((1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4-dimethylbenzoate

2-(4-amino-3-methyl-1-piperidyl)benzonitrile (350 mg, 1.63 mmol), methyl5-bromo-2,4-dimethyl-benzoate (515.13 mg, 2.12 mmol), Pd(t-Bu₃P)₂(166.60 mg, 326 umol), t-BuONa (447.92 mg, 4.89 mmol) were dissolved intoluene (10 mL) and the mixture was stirred at 100° C. for 16 hour. Themixture was cooled to rt and quenched with IM HCl, extracted with EA,the organic layer was concentrated to purified via preparative HPLC(acid) to give methyl5-[[1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoate(160 mg, 423.86 umol, 26%) as a red oil. ESI-MS (EI⁺, m/z): 378.3[M+H]⁺.

Step 5:5-((1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4-dimethylbenzoicAcid

Methyl5-[[(3R,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoate(100 mg, 264.91 umol) dissolved in MeOH (10 mL) and H₂O (3 mL) was addedLiOH.H₂O (88.93 mg, 2.12 mmol). The mixture was stirred at 60° C. for 16hour. The mixture was concentrated and acidified with IM HCl andextracted with EA. The combined organic layer were washed with brine,dried (Na₂SO₄), filtered and concentrated to give crude5-[[(3R,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (90 mg, 247.63 umol, 93%) as a yellow oil. ESI-MS (EI⁺, m/z): 364.3[M+H]⁺.

Step 6:2-(4-(5-(((3R,4S)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide

5-[[(3R,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (90 mg, 247.63 umol) and 2-piperazin-1-ylbenzenesulfonamide (68.78mg, 247.63 umol, HCl) was dissolved in DMF (5 mL). Then EDCI (73.17 mg,371.45 umol), HOBT (40.15 mg, 297.16 umol), DIEA (96.01 mg, 742.89 umol,129.74 uL) were added to the above solution. The mixture was stirred at40° C. for 16 hour. The mixture was purified via preparative HPLC togive2-[4-[5-[[(3R,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamide(40.20 mg, 68.51 umol, 27%) as a white solid. ESI-MS (EI⁺, m/z): 587.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.04-8.02 (dd, J=8.0, 1.5 Hz, 1H),7.62-7.55 (m, 2H), 7.50-7.47 (m, 1H), 7.37-7.33 (m, 2H), 7.04-6.99 (m,2H), 6.91 (s, 1H), 6.45 (s, 1H), 5.54 (s, 2H), 3.60-3.50 (m, 4H),3.12-2.92 (m, 8H), 2.68-2.64 (t, J=11.5 Hz, 4H), 2.29 (m, 1H), 2.20 (s,3H), 2.12 (s, 3H), 1.99-1.97 (m, 1H), 1.56 (m, 1H), 1.10-1.05 (dd, J=23,6.0 Hz, 3H).

Example 128:2-(4-(5-(((3R,4R)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-170

5-[[(3R,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (60 mg, 165.08 umol) and 2-piperazin-1-ylbenzenesulfonamide (45.86mg, 165.08 umol, HCl) was dissolved in DMF (5 mL). Then EDCI (48.78 mg,247.62 umol), HOBT (26.77 mg, 198.10 umol), DIEA (64 mg, 495.24 umol,86.49 uL) were added to the above solution. The mixture was stirred at40° C. for 16 hour. The mixture was purified via preparative HPLC togive2-[4-[5-[[(3R,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamide(29.60 mg, 50.45 umol, 30%) as a white solid. ESI-MS (EI⁺, m/z): 587.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.04-8.02 (dd, J=8.0, 1.5 Hz, 1H),7.62-7.55 (m, 2H), 7.50-7.47 (m, 1H), 7.37-7.33 (m, 2H), 7.04-6.99 (m,2H), 6.91 (s, 1H), 6.45 (s, 1H), 5.54 (s, 2H), 3.65 (m, 1H), 3.51 (m,4H), 3.26-3.05 (m, 7H), 2.40 (m, 1H), 2.20 (s, 3H), 2.14 (s, 3H), 2.02(m, 1H), 1.94-1.91 (m, 1H), 1.56 (m, 1H), 1.15-1.05 (dd, J=46.5, 6.5 Hz,3H).

Example 129:2-(4-(5-(((3S,4R)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-171

5-[[(3S,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (90 mg, 247.63 umol) and 2-piperazin-1-ylbenzenesulfonamide (68.78mg, 247.63 umol, HCl) was dissolved in DMF (5 mL). Then EDCI (73.17 mg,371.45 umol), HOBT (40.15 mg, 297.16 umol), DIEA (96.01 mg, 742.89 umol,129.74 uL) were added to the above solution. The mixture was stirred at30° C. for 16 hour. The mixture was purified via preparative HPLC togive2-[4-[5-[[(3S,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]benzenesulfonamide(84.80 mg, 144.52 umol, 58%) as a white solid. ESI-MS (EI⁺, m/z): 587.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.03-8.01 (dd, J=8.0, 1.5 Hz, 1H),7.62-7.55 (m, 2H), 7.50-7.47 (m, 1H), 7.37-7.33 (m, 2H), 7.04-6.99 (m,2H), 6.91 (s, 1H), 6.45 (s, 1H), 5.54 (s, 2H), 3.60-3.50 (m, 4H),3.12-2.92 (m, 8H), 2.68-2.64 (t, J=11.5 Hz, 4H), 2.29 (m, 1H), 2.20 (s,3H), 2.12 (s, 3H), 1.99-1.97 (m, 1H), 1.58 (m, 1H), 1.10-1.05 (dd,J=21.5, 6.0 Hz, 3H).

Example 130:3-(4-(5-((1-(2-cyanophenyl)piperidin-4-yl)amino)-2-methyl-4-(trifluoromethyl)benzoyl)piperazin-1-yl)pyridine-2-sulfonamide,I-172

Synthetic Scheme:

Procedures and Characterization:

Step 1: 2,4,5-trifluorobenzenesulfonamide

To a solution of 3-amino-4-(trifluoromethyl)benzoic acid (10 g, 48.75mmol) in DMF (20 mL) was added NBS (8.68 g, 48.75 mmol), after 10-20° C.for 2 hour, the solution was poured into ice-water (100 mL), extractedwith EA (50 mL×2), the solution was washed with water (100 mL×2) andbrine (100 mL), dried (Na₂SO₄) and concentrated to afford5-amino-2-bromo-4-(trifluoromethyl)benzoic acid (12.30 g, 43.31 mmol,88%) as a brown solid. ESI-MS (EI⁺, m/z): 285.8 [M+H]⁺.

Step 2: methyl 5-amino-2-bromo-4-(trifluoromethyl)benzoate

To a solution of 5-amino-2-bromo-4-(trifluoromethyl)benzoic acid (10 g,35.21 mmol) in Methanol (100 mL) was added H₂SO₄ (7 mL), the solutionwas heated to 75° C. for 17 hour, the solution was poured into ice-water(100 mL), extracted with EA (50 mL×2), the organic phase was washed withsat. NAHCO₃ solution (50 mL) and brine (50 mL), dried (Na₂SO₄) andconcentrated to afford methyl5-amino-2-bromo-4-(trifluoromethyl)benzoate (9.40 g, 31.54 mmol, 89%) asa brown solid. ESI-MS (EI⁺, m/z): 297.8 [M+H]⁺.

Step 3: methyl 5-amino-2-methyl-4-(trifluoromethyl)benzoate

A mixture of methyl 5-amino-2-bromo-4-(trifluoromethyl)benzoate (2 g,6.71 mmol), methylboronic acid (2.01 g, 33.55 mmol) and K₃PO₄ (4.27 g,20.13 mmol) in DMF (20 mL) was irradiated in the microwave at 120° C.for 2 hour, the solution was diluted with water (100 mL), extracted withEA (50 mL×2), the organic phase was washed with water (100 mL) and brine(100 mL), dried (Na₂SO₄), concentrated and purified by chromatography(silica, PE/EA=15:1) to afford methyl5-amino-2-methyl-4-(trifluoromethyl)benzoate (1.30 g, 4.79 mmol, 71.4%)as a brown solid. ESI-MS (EI⁺, m/z): 234.0 [M+H]⁺.

Step 4: methyl 5-bromo-2-methyl-4-(trifluoromethyl)benzoate

To a mixture of methyl 5-amino-2-methyl-4-(trifluoromethyl)benzoate (1g, 4.29 mmol) and CuBr₂ (1.92 g, 8.58 mmol) in ACN (40 mL) was addedIsoamyl nitrite (753.57 mg, 6.44 mmol), the solution was heated to 60°C. for 2 hour, the solution was diluted with water (100 mL), extractedwith EtOAc (50 mL×2), washed with water (50 mL) and brine (50 mL), dried(Na₂SO₄), concentrated in vacuo to afford methyl5-bromo-2-methyl-4-(trifluoromethyl)benzoate (1 g, 3.37 mmol, 78%) as abrown liquid.

Step 5: methyl5-((1-(2-cyanophenyl)piperidin-4-yl)amino)-2-methyl-4-(trifluoromethyl)benzoate

methyl 5-bromo-2-methyl-4-(trifluoromethyl)benzoate (750 mg, 2.52 mmol),2-(4-amino-1-piperidyl)benzonitrile (659.36 mg, 3.28 mmol), xantphos(145.81 mg, 252 umol), Pd₂(dba)₃ (230.83 mg, 252 umol), Cs₂CO₃ (2.46 g,7.56 mmol) were dissolved in dioxane (50 mL) and the mixture was stirredat 100° C. for 16 hour. LCMS showed our desired product. The mixture wascooled to rt, filtered and the filtrate was concentrated. The residuewas extracted between water and EA, the combined organic layer wasconcentrated. The residue was purified via preparative HPLC to givemethyl5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-4-(trifluoromethyl)benzoate(240 mg, 574.96 umol, 22%) as a yellow solid. ESI-MS (EI⁺, m/z): 418.2[M+H]⁺.

Step 6:5-((1-(2-cyanophenyl)piperidin-4-yl)amino)-2-methyl-4-(trifluoromethyl)benzoicAcid

methyl5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-4-(trifluoromethyl)benzoate(240 mg, 574.96 umol) dissolved in MeOH (10 mL) and H₂O (3 mL) was addedLiOH.H₂O (193 mg, 4.60 mmol). The mixture was stirred at 60° C. for 17hour. The mixture was concentrated and acidified with 1M HCl andextracted with EA. The organic layer was washed with brine, dried overMgSO₄, filtered and concentrated to give crude5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-4-(trifluoromethyl)benzoicacid (200 mg, 495.79 umol, 86%) as a yellow solid. ESI-MS (EI⁺, m/z):404.2 [M+H]⁺.

Step 7:3-(4-(5-((1-(2-cyanophenyl)piperidin-4-yl)amino)-2-methyl-4-(trifluoromethyl)benzoyl)piperazin-1-yl)pyridine-2-sulfonamide

5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-4-(trifluoromethyl)benzoicacid (50 mg, 123.95 umol), 3-piperazin-1-ylpyridine-2-sulfonamide (51.83mg, 185.93 umol, HCl), EDCI (36.63 mg, 185.93 umol), HOBT (20.10 mg,148.74 umol), DIEA (48.06 mg, 371.85 umol, 64.95 uL) were dissolved inDMF (3 mL) and the mixture was stirred at 30° C. for 17 hour. Themixture was filtered and purified via preparative HPLC to give3-[4-[5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-4-(trifluoromethyl)benzoyl]piperazin-1-yl]pyridine-2-sulfonamide(45.60 mg, 72.65 umol, 58%) as a white solid. ESI-MS (EI⁺, m/z): 628.3[M+H]J. ¹H NMR (500 MHz, CDCl₃) δ 8.38-8.37 (m, 1H), 7.68-7.66 (dd,J=8.0, 1.0 Hz, 1H), 7.58-7.56 (dd, J=7.5, 1.5 Hz, 1H), 7.52-7.47 (m,2H), 7.30 (s, 1H), 7.05-7.00 (m, 2H), 6.60 (s, 1H), 5.22 (s, 2H),4.26-4.25 (d, J=6.0 Hz, 1H), 4.12 (m, 1H), 3.97-3.95 (m, 1H), 3.58-3.55(m, 2H), 3.50-3.47 (m, 3H), 3.23-3.17 (m, 2H), 3.09-2.98 (m, 4H),2.23-2.19 (m, 5H), 1.81-1.74 (m, 2H).

Example 131:2-(4-(5-((1-(2-cyanophenyl)piperidin-4-yl)amino)-2-methyl-4-vinylbenzoyl)piperazin-1-yl)benzenesulfonamide,I-173

Synthetic Scheme:

Procedures and Characterization:

Step 1: 4-bromo-5-iodo-2-methylbenzoic Acid

N-Iodosuccinimide (11.51 g, 51.15 mmol) is added in portions to anice-cold solution of sulphuric acid (110.37 g, 1.13 mol, 59.98 mL). Theresulting mixture was stirred at that temperature for 40 min, then4-bromo-2-methyl-benzoic acid (10 g, 46.50 mmol) dissolved in 60 ml ofsulphuric acid is added while the temperature maintains at 0-5° C. Themixture was stirred for 1 h, then the mixture poured on crushed ice andthe resulting precipitate was washed with water ten times, heptane threetimes, dried in vacuo to afford 4-bromo-5-iodo-2-methyl-benzoic acid (12g, 35.20 mmol, 75%) as a white solid.

Step 2: methyl 4-bromo-5-iodo-2-methylbenzoate

To a solution of 4-bromo-5-iodo-2-methyl-benzoic acid (10 g, 29.33 mmol)in MeOH (100 mL) was added H₂SO₄ (18.41 g, 187.71 mmol, 10.01 mL) at rt,then the reaction mixture was stirred at 80° C. for 3 hour. Cooled tort, removed the solvent, extracted with EA (200 mL*3) and water (50mL*2), dried, concentrated to afford methyl4-bromo-5-iodo-2-methyl-benzoate (10 g, 28.17 mmol, 96%) as a pale whitesolid. ESI-MS (EI⁺, m/z): 356.8 [M+2]⁺.

Step 3: methyl4-bromo-5-((1-(2-cyanophenyl)piperidin-4-yl)amino)-2-methylbenzoate

methyl 4-bromo-5-iodo-2-methyl-benzoate (3 g, 8.45 mmol),2-(4-amino-1-piperidyl)benzonitrile (2.04 g, 10.14 mmol), Cs₂CO₃ (5.51g, 16.90 mmol), Pd₂(dba)₃ (154.83 mg, 169 umol), xantphos (195.73 mg,338 umol) were dissolved in toluene (40 mL). Then the mixture wasstirred at 80° C. for 17 hour. The mixture was cooled to rt andfiltered. To the filtrate was added water (50 mL) and the resultingmixture was extracted with EA (30 mL×3). The combined organic layer waswashed with water, brine, dried (Na₂SO₄), filtered and the filtrate wasconcentrated. The reside was purified by SGC (PE/EA=10) to give methyl4-bromo-5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-benzoate (1.70g, 3.97 mmol, 46%) as a yellow solid. ESI-MS (EI⁺, m/z): 428.1 [M+H]⁺.

Step 4:4-bromo-5-((1-(2-cyanophenyl)piperidin-4-yl)amino)-2-methylbenzoic Acid

methyl4-bromo-5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-benzoate (300mg, 700.41 umol), LiOH.H₂O (235.13 mg, 5.60 mmol) were dissolved in MeOH(10 mL) and H₂O (3 mL). Then the mixture was stirred at 60° C. for 17hour. The solvent was removed and to the residue was added water (50 mL)and the resulting mixture was extracted with EA (30 mL×3). The combinedorganic layer was washed with water, brine, dried (Na₂SO₄), filtered andthe filtrate was concentrated to give4-bromo-5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-benzoic acid(290 mg, 699.99 umol, 99%) as a yellow solid. ESI-MS (EI⁺, m/z): 416.1[M+2]⁺.

Step 5:2-(4-(4-bromo-5-((1-(2-cyanophenyl)piperidin-4-yl)amino)-2-methylbenzoyl)piperazin-1-yl)benzenesulfonamide

4-bromo-5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-benzoic acid(290 mg, 699.98 umol), 2-piperazin-1-ylbenzenesulfonamide (291.65 mg,1.05 mmol, HCl), HOBT (94.58 mg, 699.98 umol), EDCI (134.19 mg, 699.98umol), DIEA (452.33 mg, 3.50 mmol, 611.26 uL) were dissolved in DMF (5mL). Then the mixture was stirred at 30° C. for 17 hour. Water (50 mL)was added and the resulting mixture was filtered, the solid was dried togive2-[4-[4-bromo-5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-benzoyl]piperazin-1-yl]benzenesulfonamide(420 mg, 526.98 umol, 75%) as a brown oil. ESI-MS (EI⁺, m/z): 637.2[M+H]⁺.

Step 6:2-(4-(5-((1-(2-cyanophenyl)piperidin-4-yl)amino)-2-methyl-4-vinylbenzoyl)piperazin-1-yl)benzenesulfonamide

2-[4-[4-bromo-5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-benzoyl]piperazin-1-yl]benzenesulfonamide(440 mg, 690.10 umol), Vinyltrifluoroboric acid potassium (184.88 mg,1.38 mmol), K₂CO₃ (286.14 mg, 2.07 mmol), Pd(dppf)Cl₂ (16.91 mg, 20.70umol) were dissolved in ACN (10 mL) and H₂O (4 mL). Then the mixture wasstirred at 80° C. for 17 hour. The mixture was filtered and the filtratewas purified via preparative HPLC to give2-[4-[5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2-methyl-4-vinyl-benzoyl]piperazin-1-yl]benzenesulfonamide(100 mg, 171.02 umol, 24%) as a yellow solid. ESI-MS (EI⁺, m/z): 585.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.03 (m, 1H), 7.62-7.55 (m, 2H),7.50-7.47 (m, 1H), 7.39-7.33 (m, 2H), 7.10 (s, 1H), 7.04-6.99 (m, 2H),6.72-6.66 (m, 1H), 6.51 (s, 1H), 5.63-5.59 (dd, J=12, 1.0 Hz, 1H), 5.52(s, 1H), 4.26-4.25 (dd, J=10.5, 1.0 Hz, 1H), 3.71-3.47 (m, 6H),3.17-2.95 (m, 6H), 2.23 (m, 5H), 1.78-1.58 (m, 2H).

Example 132:2-(4-(5-((1-(2-cyanophenyl)piperidin-4-yl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)-3,5-difluorobenzenesulfonamide,I-174

Synthetic Scheme:

Procedures and Characterization:

Step 1: 5,7-difluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide

To a solution of N-(oxomethylene)sulfamoyl chloride (6.36 g, 44.92 mmol,3.90 mL) in CH₃NO₂ (50 mL) was added 2,4-difluoroaniline (5 g, 38.73mmol, 3.94 mL) at −42° C., and the mixture was stirred at −42° C. for 1hour. Then AlCl₃ (6.45 g, 48.41 mmol) was added and the mixture wasstirred at 100° C. for 1 hour. The mixture was poured onto ice-water,and stirred for 10 min, extracted with EA (400 mL), the organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was suspended in aqueous sodium bicarbonate (10 g/200 mL ofwater). The suspension was heated until most of the precipitatedissolved, treated with charcoal and filtered. The pH of the filtratewas adjusted to pH-1 using 6 M hydrochloric acid and extracted with EA(400 mL), the organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to give crude5,7-difluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one (3.5 g, 14.95 mmol,38%) as a yellow solid.

Step 2: 2-amino-3,5-difluorobenzenesulfonamide

5,7-difluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one (3.5 g, 14.95 mmol)was added to aqueous Sulfuric Acid (10 mL) and water (10 mL). Theresulting mixture was stirred at 120° C. for 17 hour until a clearsolution was obtained. The reaction mixture was cooled to 0° C., and thepH was adjusted to pH˜7 using aqueous sodium hydroxide (30 percent w/v)and extracted with EtOAc (500 mL×2). The combined organic layers weredried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by chromatography (silica, ethyl acetate/petroleum ether=1/1)to afford 2-amino-3,5-difluoro-benzenesulfonamide (1 g, 4.80 mmol, 32%)as a yellow solid. ESI-MS (EI⁺, m/z): 209.1 [M+H]⁺.

Step 3: 2-amino-3,5-3,5-difluoro-2-(piperazin-1-yl)benzenesulfonamide

To a solution of 2-amino-3,5-difluoro-benzenesulfonamide (1.2 g, 5.76mmol) in n-BuOH (20 mL) was added 2-bromo-N-(2-bromoethyl)ethanamine(3.8 g, 12.19 mmol, HBr), then the mixture was stirred at 125° C. for 48hour. The solvent was concentrated, the residue was adjusted pH˜8 withaq.NaOH (3M). Then mixture was concentrated. Then DMF (10 mL) was addedand purified via preparative HPLC to give crude3,5-difluoro-2-piperazin-1-yl-benzenesulfonamide (120 mg, 333.22 umol,5%, 77% purity) as a white solid. ESI-MS (EI⁺, m/z): 278.2 [M+H]⁺.

Step 4:2-(4-(5-((1-(2-cyanophenyl)piperidin-4-yl)amino)-2,4-dimethylbenzoyl)piperazin-1-yl)-3,5-difluorobenzenesulfonamide

3,5-difluoro-2-piperazin-1-yl-benzenesulfonamide (98 mg, 353.42 umol),5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoic acid(148.19 mg, 424.10 umol), EDCI (101.63 mg, 530.13 umol), HOBT (62.08 mg,459.45 umol), DIEA (274.06 mg, 2.12 mmol, 369.36 uL) were dissolved inDMF (5 mL). Then the mixture was stirred at 25° C. for 17 hour. Themixture was filtered and the filtrate was purified via preparative HPLCto give2-[4-[5-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]-3,5-difluoro-benzenesulfonamide(91.2 mg, 149.83 umol, 42%) as a white solid. ESI-MS (EI⁺, m/z): 609.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.57-7.56 (d, J=7.5 Hz, 2H), 7.51-7.48(t, 1H), 7.08-7.00 (m, 3H), 6.93-6.90 (d, J=11 Hz, 1H), 6.55-6.41 (d,J=18 Hz, 1H), 5.50 (s, 2H), 4.92-4.90 (m, 1H), 3.63-3.39 (m, 6H),3.29-3.25 (m, 1H), 3.17-3.13 (m, 2H), 3.02-2.96 (m, 4H), 2.25-2.11 (m,8H), 1.77-1.59 (m, 2H).

Example 133:(R)-(3-(4-(3-((1-(3-chloropyridin-2-yl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridin-2-yl)(imino)(methyl)-λ⁶-sulfanoneTrifluoroacetate Salt, I-175

Synthetic Scheme:

Procedures and Characterization:

Step 1:(R)-(3-(4-(3-((1-(3-chloropyridin-2-yl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridin-2-yl)(imino)(methyl)-λ⁶-sulfanone

3-[[1-(3-chloro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (50 mg, 133.73 umol), tert-butyl(R)-(methyl(oxo)(3-(piperazin-1-yl)pyridin-2-yl)-λ⁶-sulfanylidene)carbamate(45.53 mg, 133.73 umol), HOBT (36.14 mg, 267.46 umol), EDCI (51.27 mg,267.46 umol), DIEA (86.42 mg, 668.65 umol, 116.78 uL) were dissolved inDMF (5 mL). Then the mixture was stirred at 27° C. for 17 hour. Themixture was filtered and the filtrate was purified via preparative HPLCto give tert-butylN-[[3-[4-[3-[[1-(3-chloro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]piperazin-1-yl]-2-pyridyl]-methyl-oxo-$l{circumflexover ( )}{6}-sulfanylidene]carbamate (20 mg, 28.72 umol, 21%) as a whitesolid. ESI-MS (EI⁺, m/z): 696.3 [M+H]⁺.

Step 2:(R)-(3-(4-(3-((1-(3-chloropyridin-2-yl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridin-2-yl)(imino)(methyl)-16-sulfanoneTrifluoroacetate Salt

tert-butylN-[[3-[4-[3-[[1-(3-chloro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]piperazin-1-yl]-2-pyridyl]-methyl-oxo-$l{circumflexover ( )}{6}-sulfanylidene]carbamate (20 mg, 28.72 umol) was dissolvedin TFA (1 mL) and DCM (5 mL). The mixture was stirred at 25° C. for 3hour. The solvent was removed and the residue was purified viapreparative HPLC to give[3-[[1-(3-chloro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-phenyl]-[4-[2-(methylsulfonimidoyl)-3-pyridyl]piperazin-1-yl]methanone(16.40 mg, 23.09 umol, 80%, TFA) as a white solid. ESI-MS (EI⁺, m/z):596.2 [M+H]⁺. ¹H-NMR (500 MHz, CD₃OD) δ 8.58 (m, 1H), 8.23-8.17 (m, 2H),7.83-7.76 (m, 2H), 7.24 (s, 1H), 7.01-6.99 (m, 1H), 4.11 (m, 2H),4.04-3.94 (m, 2H), 3.81 (s, 3H), 3.62 (m, 1H), 3.48 (m, 2H), 3.29-3.26(m, 2H), 3.12-3.07 (m, 2H), 2.95-2.89 (m, 2H), 2.51 (s, 3H), 2.42 (s,3H), 2.33 (s, 3H), 2.16-2.05 (m, 5H).

Example 134:(3-(4-(3-((1-(3-chloropyridin-2-yl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridin-2-yl)(imino)(methyl)-16-sulfanoneTrifluoroacetate Salt, I-176

Synthetic Scheme:

Procedures and characterization:

Step 1: tert-butyl((3-(4-(3-((1-(3-chloropyridin-2-yl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate

3-[[1-(3-chloro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (50 mg, 133.73 umol), tert-butyl(S)-(methyl(oxo)(3-(piperazin-1-yl)pyridin-2-yl)-λ⁶-sulfanylidene)carbamate(68.29 mg, 200.59 umol), HOBT (36.14 mg, 267.46 umol), EDCI (51.27 mg,267.46 umol), DIEA (86.42 mg, 668.65 umol, 116.78 uL) were dissolved inDMF (5 mL). Then the mixture was stirred at 27° C. for 17 hour. Themixture was filtered and the filtrate was purified via preparative HPLCto give tert-butyl((3-(4-(3-((1-(3-chloropyridin-2-yl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridin-2-yl)(methyl)(oxo)-λ⁶-sulfanylidene)carbamate(20 mg, 28.72 umol, 21%) as a white solid. ESI-MS (EI⁺, m/z): 696.3[M+H]⁺.

Step 2:(3-(4-(3-((1-(3-chloropyridin-2-yl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridin-2-yl)(imino)(methyl)-16-sulfanonetrifluoroacetate Salt

tert-butyl((3-(4-(3-((1-(3-chloropyridin-2-yl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridin-2-yl)(methyl)(oxo)-λ⁶-sulfanylidene)carbamate(25 mg, 35.90 umol) was dissolved in TFA (1 mL) and DCM (5 mL). Themixture was stirred at 25° C. for 3 hour. The solvent was removed andthe residue was purified via preparative HPLC to give[3-[[1-(3-chloro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-phenyl]-[4-[2-(methylsulfonimidoyl)-3-pyridyl]piperazin-1-yl]methanone(21.70 mg, 30.55 umol, 85%, TFA) as a white solid. ESI-MS (EI⁺, m/z):596.2 [M+H]⁺. ¹H-NMR (500 MHz, MeOD) δ 8.56 (m, 1H), 8.20-8.17 (m, 2H),7.81-7.76 (m, 2H), 7.23 (s, 1H), 7.02-6.99 (m, 1H), 4.21-3.94 (m, 4H),3.78-3.75 (m, 3H), 3.62 (m, 1H), 3.48 (m, 2H), 3.29-3.26 (m, 2H),3.14-3.05 (m, 2H), 2.95-2.90 (m, 2H), 2.51 (s, 3H), 2.42 (s, 3H), 2.33(s, 3H), 2.18-2.04 (m, 5H).

Example 135:(S)-2-(4-((5-(3-(hydroxymethyl)-4-(1,3,4-oxadiazol-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenyl)amino)piperidin-1-yl)benzonitrile,I-177

Synthetic Scheme:

Procedures and Characterization:

Step 1: 4-benzyl 1-(tert-butyl)(S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate

benzyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (3 g, 11.99 mmol),di-tert-butyl dicarbonate (5.23 g, 23.98 mmol), Na₂CO₃ (5.08 g, 47.96mmol) were dissolved in THF (20 mL) and H₂O (10 mL). Then the mixturewas stirred at 30° C. for 4 hour. EA (100 mL) was added to the reactionand extracted with EA, the organic layer was dried (Na₂SO₄), filteredand the filtrate was concentrated. The residue was purified by SGC(PE/EA=1) to give 4-benzyl 1-tert-butyl(2S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (3.80 g, 10.84 mmol,90%) as a colorless oil. ESI-MS (EI⁺, m/z): 251.4 [M−100+H]⁺.

Step 2: 4-benzyl 1-(tert-butyl)(S)-2-((benzyloxy)methyl)piperazine-1,4-dicarboxylate

4-benzyl 1-tert-butyl (2S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate(2.80 g, 7.99 mmol), (bromomethyl)benzene (2.05 g, 11.99 mmol), TBAI(1.48 g, 4 mmol) were dissolved in DCM (20 mL). Then Ag₂O (2.22 g, 9.59mmol, 311.22 uL) was added. The mixture was stirred at rt for 17 hour.Filtered and the filtrate was concentrated, the residue was purified bySGC (PE/EA=5) to give 4-benzyl 1-tert-butyl(2S)-2-(benzyloxymethyl)piperazine-1,4-dicarboxylate (2.50 g, 5.67 mmol,71%) as a colorless oil. ESI-MS (EI⁺, m/z): 463.3 [M+Na]⁺.

Step 3: benzyl (S)-3-((benzyloxy)methyl)piperazine-1-carboxylate

4-benzyl I-(tert-butyl)(S)-2-((benzyloxy)methyl)piperazine-1,4-dicarboxylate (2.80 g, 7.99 mmolwas dissolved in DCM (10 mL) and TFA (8 mL), the mixture was stirred atrt for 17 hour. The solvent was concentrated and the residue was pouredonto ice water, then adjusted pH˜8 with sat.NaHCO₃. The mixture wasextracted with DCM (100 mL), the organic layer was washed with water,brine, dried (Na₂SO₄) and filtered to concentrate to give crude benzyl(3S)-3-(benzyloxymethyl)piperazine-1-carboxylate (2.20 g, 6.46 mmol,86%) as a yellow oil. ESI-MS (EI⁺, m/z): 341.2 [M+H]⁺.

Step 4: 4-benzyl 1-(4-nitrophenyl)(S)-2-((benzyloxy)methyl)piperazine-1,4-dicarboxylate

benzyl (3S)-3-(benzyloxymethyl)piperazine-1-carboxylate (2.30 g, 6.76mmol), (4-nitrophenyl) carbonochloridate (2.72 g, 13.51 mmol), pyridine(2.67 g, 33.78 mmol, 2.73 mL) was dissolved in DCM (30 mL). The mixturewas stirred at 30° C. for 17 hour. Water was added and extracted withDCM (50 mL), the organic layer was concentrated. The residue waspurified by SGC (PE/EA=5) to give 4-benzyl 1-(4-nitrophenyl)(2S)-2-(benzyloxymethyl)piperazine-1,4-dicarboxylate (3 g, 5.93 mmol,87%) as a yellow oil. ESI-MS (EI⁺, m/z): 506.2 [M+H]⁺.

Step 5: benzyl(S)-3-((benzyloxy)methyl)-4-(hydrazinecarbonyl)piperazine-1-carboxylate

4-benzyl 1-(4-nitrophenyl)(2S)-2-(benzyloxymethyl)piperazine-1,4-dicarboxylate (3 g, 5.93 mmol),Hydrazine hydrate (1.11 g, 17.80 mmol) were dissolved in DMF (10 mL).Then the mixture was stirred at 25° C. for 17 hour. The mixture wasadded water (50 mL) and extracted with EA (30 mL×3). The combinedorganic layer was washed with water, brine, dried (Na₂SO₄), filtered andthe filtrate was concentrated. The reside was purified by Prep-TLC(DCM/MeOH=10) to give benzyl(3S)-3-(benzyloxymethyl)-4-(hydrazinecarbonyl)piperazine-1-carboxylate(2 g, 3.51 mmol, 59%, 70% purity) as a yellow oil. ESI-MS (EI⁺, m/z):399.3 [M+H]⁺.

Step 6: benzyl(S)-3-((benzyloxy)methyl)-4-(2-formylhydrazine-1-carbonyl)piperazine-1-carboxylate

Formic acid (8.24 g, 178.99 mmol, 6.75 mL), acetyl acetate (12.13 g,118.88 mmol, I mL) were mixed and stirred at 60° C. for 3 hour, then themixture was cooled to rt, and 1.5 mL this mixture was added to asolution of benzyl(3S)-3-(benzyloxymethyl)-4-(hydrazinecarbonyl)piperazine-1-carboxylate(1.80 g, 4.52 mmol) in THF (20 mL). The mixture was stirred at 25° C.for 17 hour. The mixture was added water (50 mL) and extracted with EA(30 mL×3). The combined organic layer was washed with water, brine,dried (Na₂SO₄), filtered and the filtrate was concentrated. The residewas purified by SGC (DCM/MeOH=15) to give benzyl(3S)-3-(benzyloxymethyl)-4-(formamidocarbamoyl)piperazine-1-carboxylate(1.60 g, 3.75 mmol, 83%) as a yellow oil. ESI-MS (EI⁺, m/z): 427.3[M+H]⁺.

Step 7: benzyl(S)-3-((benzyloxy)methyl)-4-(1,3,4-oxadiazol-2-yl)piperazine-1-carboxylate

benzyl (3S)-3-(benzyloxymethyl)-4-(formamidocarbamoyl)piperazine-1-carboxylate(1.60 g, 3.75 mmol), PPh₃ (1.97 g, 7.50 mmol), TEA (1.14 g, 11.25 mmol,1.56 mL) were dissolved in CCl₄ (10 mL) and DCM (10 mL). Then themixture was stirred at 70° C. for 5 hour. The mixture was filtered andthe filtrate was purified via preparative HPLC to give benzyl(3S)-3-(benzyloxymethyl)-4-(1,3,4-oxadiazol-2-yl)piperazine-1-carboxylate(600 mg, 734.48 umol, 19%, 50% purity) as a white solid. ESI-MS (EI⁺,m/z): 409.3 [M+H]⁺.

Step 8: (S)-2-(2-((benzyloxy)methyl)piperazin-1-yl)-1,3,4-oxadiazole

benzyl(3S)-3-(benzyloxymethyl)-4-(1,3,4-oxadiazol-2-yl)piperazine-1-carboxylate(600 mg, 1.47 mmol), Pd/C (500 mg, 411.60 umol, 10% purity) weredissolved in EtOH (20 mL). Then the mixture was stirred at 25° C. for 24hour under H₂. The mixture was filtered and concentrated to give crude2-[(2S)-2-(benzyloxymethyl)piperazin-1-yl]-1,3,4-oxadiazole (430 mg,1.41 mmol, 95%, 90% purity) as a colorless oil. ESI-MS (EI⁺, m/z): 275.3[M+H]⁺.

Step 9:(S)-2-(4-((3-(3-((benzyloxy)methyl)-4-(1,3,4-oxadiazol-2-yl)piperazine-1-carbonyl)-2,4,6-trimethylphenyl)amino)piperidin-1-yl)benzonitrile

2-[(2S)-2-(benzyloxymethyl)piperazin-1-yl]-1,3,4-oxadiazole (330 mg,1.20 mmol),3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoic acid(654.21 mg, 1.80 mmol), HOBT (324.29 mg, 2.40 mmol), EDCI (459.60 mg,2.40 mmol), DIEA (1.24 g, 9.60 mmol, 1.68 mL), DMAP (14.66 mg, 120 umol)were dissolved in DMF (10 mL). Then the mixture was stirred at 40° C.for 48 hour. The mixture was cooled to rt added water (50 mL) andextracted with EA (30 mL×3). The combined organic layer was washed withwater, brine, dried (Na₂SO₄), filtered and the filtrate wasconcentrated. The reside was purified by SGC (DCM/MeOH=50) to give2-[4-[3-[(3S)-3-(benzyloxymethyl)-4-(1,3,4-oxadiazol-2-yl)piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]benzonitrile(340 mg, 427.91 umol, 35%, 78% purity) as a yellow solid. ESI-MS (EI⁺,m/z): 620.3 [M+H]⁺.

Step 10:(S)-2-(4-((5-(3-(hydroxymethyl)-4-(1,3,4-oxadiazol-2-yl)piperazine-1-carbonyl)-2,4-dimethylphenyl)amino)piperidin-1-yl)benzonitril

2-[4-[3-[(3S)-3-(benzyloxymethyl)-4-(1,3,4-oxadiazol-2-yl)piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]benzonitrile(250 mg, 403.39 umol), BBr₃ (2.95 g, 2 mmol, 2 mL, 17% purity) weredissolved in DCM (5 mL). The mixture was stirred at 20° C. for 3 hour.MeOH (5 mL) was added and DCM (10 mL×3) was added and washed withaq.NaHCO₃. The organic layer was concentrated. The residue was purifiedvia preparative HPLC to get 2-[4-[3-[(3S)-3-(hydroxymethyl)-4-(1,3,4-oxadiazol-2-yl)piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]benzonitrile(92 mg, 173.71 umol, 43%) as a white solid. ESI-MS (EI⁺, m/z): 530.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.95 (s, 1H), 7.55-7.45 (m, 2H),7.00-6.97 (m, 2H), 6.89-6.85 (m, 1H), 4.84-4.81 (m, 1H), 4.25 (m, 1H),3.92-3.72 (m, 4H), 3.57-3.40 (m, 4H), 3.40-2.74 (m, 7H), 2.27-2.20 (m,6H), 2.12-2.09 (m, 3H), 2.03-2.00 (m, 2H), 1.71-1.67 (m, 2H).

Example 136:2-(4-(3-(((3R,4S)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide,I-178

Synthetic Scheme:

Procedures and Characterization:

Step 1: methyl3-((1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoate

2-(4-amino-3-methyl-1-piperidyl)benzonitrile (4.60 g, 21.37 mmol) methyl3-bromo-2,4,6-trimethyl-benzoate (6.59 g, 25.64 mmol), Pd(t-Bu₃P)₂ (1.09g, 2.14 mmol), t-BuONa (5.87 g, 64.11 mmol) was dissolved in toluene(150 mL) and the mixture was stirred at 110° C. for 17 hour. The mixturewas cooled to rt and filtered. The filtrate was concentrated and theresidue was purified by SGC (PE/EA=10) to give methyl3-[[1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoate(6 g, 15.33 mmol, 71%) as a red oil. ESI-MS (EI⁺, m/z): 392.3 [M+H]⁺.

Step 2: methyl3-(((3R,4S)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoate

methyl3-[[(3R,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoate(1.50 g, 3.83 mmol), BBr₃ (28.22 g, 19.15 mmol, 19 mL, 17% purity) weredissolved in DCM (10 mL). Then the mixture was stirred at −40-20° C. for3 hour. The solvent was removed and the residue was added water (50 mL)and extracted with DCM (30 mL×3). The combined organic layer was washedwith water, brine, dried (Na₂SO₄), filtered and the filtrate wasconcentrated to give3-[[(3R,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (1.20 g, 3.18 mmol, 83%) as a red solid. ESI-MS (EI⁺, m/z): 378.3[M+H]⁺.

Step 3:2-(4-(3-(((3R,4S)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide

3-[[(3R,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (150 mg, 397.37 umol), 2-piperazin-1-ylpyridine-3-sulfonamide(166.16 mg, 596.06 umol, HCl), HOBT (107.39 mg, 794.74 umol), EDCI(152.35 mg, 794.74 umol), DIEA (308.14 mg, 2.38 mmol, 416.41 uL) weredissolved in DMF (3 mL). Then the mixture was stirred at 20° C. for 17hour. The mixture was filtered and the filtrate was purified viapreparative HPLC to give2-[4-[3-[[(3R,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]piperazin-1-yl]pyridine-3-sulfonamide(131 mg, 217.69 umol, 54%) as a white solid. ESI-MS (EI⁺, m/z): 602.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.56-8.54 (m, 1H), 8.28-8.26 (m, 1H),7.54-7.52 (d, J=8.0 Hz, 1H), 7.47-7.24 (m, 1H), 7.27-7.24 (m, 1H),6.99-6.96 (m, 2H), 6.85 (d, J=2.5 Hz, 1H), 5.65 (s, 2H), 4.04-3.99 (m,2H), 3.58-3.46 (m, 2H), 3.39-3.31 (m, 4H), 3.15-3.10 (m, 2H), 2.80-2.54(m, 4H), 2.27-2.17 (m, 9H), 1.87-1.76 (m, 2H), 1.62-1.51 (m, 1H),1.22-1.17 (dd, J=16, 6.5 Hz, 3H).

Example 137:2-(4-(3-(((3S,4R)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamideI-179

Synthetic Scheme:

Procedures and Characterization:

Step 1:3-(((3S,4R)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoicAcid

methyl3-[[(3S,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoate(300 mg, 766.28 umol), BBr₃ (2.94 g, 2 mmol, 2 mL, 17% purity) weredissolved in DCM (5 mL). Then the mixture was stirred at −40-20° C. for3 hour. The solvent was evaporated and to the residue was added water(50 mL) and the resulting mixture was extracted with DCM (30 mL×3). Thecombined organic layers were washed with water, brine, dried (Na₂SO₄),filtered and the filtrate was concentrated to give3-[[(3S,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (220 mg, 582.81 umol, 76%) as a white solid. ESI-MS (EI⁺, m/z):278.3 [M+H]⁺.

Step 2:2-(4-(3-(((3S,4R)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide

3-[[(3R,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (150 mg, 397.37 umol), 2-piperazin-1-ylpyridine3-[[(3S,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (220 mg, 582.81 umol), 2-piperazin-1-ylpyridine-3-sulfonamide(243.70 mg, 874.21 umol, HCl), HOBT (157.50 mg, 1.17 mmol), EDCI (223.45mg, 1.17 mmol), DIEA (451.94 mg, 3.50 mmol, 610.73 uL) were dissolved inDMF (5 mL). Then the mixture was stirred at 20° C. for 17 hour. Themixture was filtered and the filtrate was purified via preparative HPLCto give2-[4-[3-[[(3S,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]piperazin-1-yl]pyridine-3-sulfonamide(192.10 mg, 319.23 umol, 54%) as a white solid. ESI-MS (EI⁺, m/z): 602.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.56-8.54 (m, 1H), 8.28-8.26 (m, 1H),7.54-7.52 (d, J=8.0 Hz, 1H), 7.47-7.44 (m, 1H), 7.27-7.24 (m, 1H),6.99-6.96 (m, 2H), 6.85 (d, J=2.5 Hz, 1H), 5.58 (s, 2H), 4.07-3.99 (m,2H), 3.58-3.46 (m, 2H), 3.39-3.31 (m, 4H), 3.15-3.10 (m, 2H), 2.80-2.54(m, 4H), 2.27-2.17 (m, 9H), 1.87-1.76 (m, 2H), 1.62-1.51 (m, 1H),1.22-1.17 (dd, J=16, 6.5 Hz, 3H).

Example 138:2-(4-(3-(((3R,4R)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide,I-180

Synthetic Scheme:

Procedures and Characterization:

Step 1:3-(((3R,4R)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoicAcid

methyl3-[[(3R,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoate(500 mg, 1.28 mmol), BBr₃ (9.43 g, 6.40 mmol, 5 mL, 17% purity) weredissolved in DCM (5 mL). Then the mixture was stirred at −40-20° C. for3 hour. The solvent was evaporated and to the residue was added water(50 mL) and extracted with DCM (30 mL×3). The combined organic layer waswashed with water, brine, dried (Na₂SO₄), filtered and the filtrate wasconcentrated to give3-[[(3R,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (460 mg, 1.22 mmol, 95%) as a red solid. ESI-MS (EI⁺, m/z): 278.3[M+H]⁺.

Step 2:2-(4-(3-(((3R,4R)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide

3-[[(3R,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (150 mg, 397.37 umol), 2-piperazin-1-ylpyridine-3-sulfonamide(166.16 mg, 596.06 umol, HCl), HOBT (107.39 mg, 794.74 umol), EDCI(152.35 mg, 794.74 umol), DIEA (308.14 mg, 2.38 mmol, 0.42 uL) weredissolved in DMF (5 mL). Then the mixture was stirred at 20° C. for 17hour. The mixture was filtered and the filtrate was purified viapreparative HPLC to give2-[4-[3-[[(3R,4R)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]piperazin-1-yl]pyridine-3-sulfonamide(82.30 mg, 136.77 umol, 34%) as a white solid. ESI-MS (EI⁺, m/z): 602.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.57-8.55 (m, 1H), 8.30-8.28 (m, 1H),7.55-7.53 (m, 1H), 7.47-7.44 (m, 1H), 7.28-7.26 (m, 1H), 7.00-6.97 (m,2H), 6.86 (s, 1H), 5.56 (s, 2H), 4.05-4.01 (m, 2H), 3.46-3.32 (m, 6H),3.19-2.99 (m, 5H), 3.32-3.22 (m, 1H), 2.27-2.18 (m, 10H), 1.89 (m, 1H),1.68-1.66 (m, 1H), 1.30-1.25 (dd, J=16, 7.0 Hz, 3H).

Example 139:2-(4-(3-(((3S,4S)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide,I-181

Synthetic Scheme:

Procedures and Characterization:

Step 1:3-(((3S,4S)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6trimethylbenzoic Acid

methyl3-[[(3S,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoate(550 mg, 1.40 mmol), BBr₃ (6.23 g, 4.23 mmol, 6 mL, 17% purity) weredissolved in DCM (5 mL). Then the mixture was stirred at −40-20° C. for3 hour. The solvent was evaporated and the residue was added water (50mL) and extracted with DCM (30 mL×3). The combined organic layer waswashed with water, brine, dried (Na₂SO₄), filtered and the filtrate wasconcentrated to give 3-[[(3S,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (470 mg, 1.25 mmol, 88%) as a red solid. ESI-MS (EI⁺, m/z): 278.3[M+H]⁺.

Step 2:2-(4-(3-(((3S,4S)-1-(2-cyanophenyl)-3-methylpiperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide

3-[[(3S,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (150 mg, 397.37 umol), 2-piperazin-1-ylpyridine-3-sulfonamide(166.16 mg, 596.06 umol, HCl), HOBT (107.39 mg, 794.74 umol), EDCI(152.35 mg, 794.74 umol), DIEA (308.14 mg, 2.38 mmol, 0.42 uL) weredissolved in DMF (5 mL). Then the mixture was stirred at 20° C. for 17hour. The mixture was filtered and the filtrate was purified viapreparative HPLC to give2-[4-[3-[[(3S,4S)-1-(2-cyanophenyl)-3-methyl-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]piperazin-1-yl]pyridine-3-sulfonamide(82.30 mg, 136.77 umol, 34%) as a white solid. ESI-MS (EI⁺, m/z): 602.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.56-8.54 (m, 1H), 8.28-8.26 (m, 1H),7.55-7.53 (m, 1H), 7.45-7.44 (m, 1H), 7.27-7.25 (m, 1H), 7.00-6.97 (m,2H), 6.85 (s, 1H), 5.66 (s, 2H), 4.05-4.01 (m, 2H), 3.46-3.32 (m, 6H),3.19-2.99 (m, 5H), 3.32-3.22 (m, 1H), 2.27-2.18 (m, 10H), 1.89 (m, 1H),1.68-1.66 (m, 1H), 1.29-1.25 (dd, J=15.5, 8.0 Hz, 3H).

Example 140:(S)-2-(4-(3-((1-(2-cyano-4-fluorophenyl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)-3-methylpiperazin-1-yl)-6-fluorobenzenesulfonamide,I-182

Procedures and Characterization:

Step 1:3-((1-(2-cyano-4-fluorophenyl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoicAcid

A mixture of methyl3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoate(20 g, 50.57 mmol) in DCM (40 mL) was cooled down to −40° C., BBr₃(41.05 g, 163.87 mmol, 15.79 mL) was added into it, the resultingmixture was kept stirring at 10° C. for 2 hour. The mixture was quenchedwith ice-water, dissolved in water (50 mL), adjusted pH˜5 with Na₂CO₃,extracted with DCM (1.5 L*2), the organic layer was washed with water(500 mL), brine, dried over Na₂SO₄, filtrated and concentrated by vacuoto give product3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (19 g, 49.81 mmol, 98%) was yellow solid. ESI-MS (EI⁺, m/z): 382.1[M+H]⁺.

Step 2:3-((1-(2-cyano-4-fluorophenyl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoylChloride

A mixture of3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (200 mg, 524.33 umol) in DCM (5 mL) was added SOCl₂ (0.5 mL), thenstirred at 20° C. for 2 hour. The mixture was concentrated to obtain3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (200 mg, 500.14 umol, 95%) as yellow solid, which was used inthe next step without further purification.

Step 3:(S)-2-(4-(3-((1-(2-cyano-4-fluorophenyl)piperidin-4-yl)amino)-2,4,6-trimethylbenzoyl)-3-methylpiperazin-1-yl)-6-fluorobenzenesulfonamide

2-fluoro-6-[(3S)-3-methylpiperazin-1-yl]benzenesulfonamide (140 mg,512.21 umol),3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (204.83 mg, 512.21 umol), DIEA (330.99 mg, 2.56 mmol, 446.08uL) were dissolved in DCM (5 mL). Then the mixture was stirred at 20° C.for 17 hour. The mixture was purified via preparative HPLC to give2-[(3S)-4-[3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-benzenesulfonamide(17.6 mg, 27.64 umol, 5%) as a white solid. ESI-MS (EI⁺, m/z): 637.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.56-7.44 (m, 1H), 7.30-7.16 (m, 1H),7.09-6.96 (m, 3H), 6.91-6.85 (m, 1H), 5.76-5.72 (m, 2H), 5.21-4.82 (m,1H), 3.78-3.52 (m, 1H), 3.47-3.17 (m, 5H), 3.03-2.57 (m, 5H), 2.29-2.22(m, 7H), 2.21-1.96 (m, 5H), 1.75-1.58 (m, 3H), 1.52-1.48 (m, 2H),1.36-1.32 (m, 1H).

Example 141:(S)-(2,4-dimethyl-5-(1-(2-(trifluoromethoxy)phenyl)piperidin-4-ylamino)phenyl)(3-(hydroxymethyl)-4-(pyridin-2-yl)piperazin-1-yl)methanone,I-183

Synthetic Scheme:

Procedures and Characterization:

Step 1: tert-butyl 1-(2-(trifluoromethoxy)phenyl)piperidin-4-ylcarbamate

A mixture of 1-bromo-2-(trifluoromethoxy)benzene (2.40 g, 9.96 mmol),tert-butyl N-(4-piperidyl)carbamate (1.99 g, 9.96 mmol), Pd₂(dba)₃ (546mg, 597 umol), BINAP (744 mg, 1.20 mmol), ^(t)-BuONa (6.47 g, 69 mmol)in toluene (50 mL) was stirred at 90° C. for 16 h. Cooled to rt,filtered and concentrated, eluted with EtOAc (50 mL), washed with H₂O(100 mL), then extracted with EtOAc (100 mL×3), washed with brine (50mL×2), dried, concentrated to afford methyl5-formyl-2,4-dimethylbenzoate (1.6 g, 32.6%) as brown gum. ESI-MS (EI+,m/z): 361 [M+H]⁺.

Step 2: 1-(2-(trifluoromethoxy)phenyl)piperidin-4-amine

A mixture of tert-butylN-[1-[2-(trifluoromethoxy)phenyl]-4-piperidyl]carbamate (1.6 g, 4.44mmol) in HCl in dioxane (4 M, 28 mmol, 7 mL) was stirred at 25° C. for 2h. The mixture was cooled to rt, quenched with water (50 mL), extractedwith EtOAc (100 mL×3), the pH was adjusted to 8-9, extracted withCH₂Cl₂/CH₃OH=10/1(50 mL×3), dried and concentrated to obtain1-[2-(trifluoromethoxy)phenyl]piperidin-4-amine (273 mg, 23.65%). ESI-MS(EI+, m/z): 261 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 7.32-7.21 (m, 2H),7.13 (dd, J=8.0, 1.3 Hz, 1H), 7.06-6.99 (m, 1H), 3.25 (d, J=12.1 Hz,2H), 2.68 (d, J=10.5 Hz, 4H), 1.80 (d, J=10.9 Hz, 2H), 1.36 (m, 2H).

Step 3: methyl2,4-dimethyl-5-(1-(2-trifluoromethoxyphenyl)piperidin-4-yl-amino)benzoate

1-[2-(trifluoromethoxy)phenyl]piperidin-4-amine (276 mg, 1.06 mmol),methyl 5-bromo-2,4-dimethyl-benzoate (257 mg, 1.06 mmol), Pd₂(dba)₃ (58mg, 63 umol), BrettPhos (79 mg, 127 umol), Cs₂CO₃ (482 mg, 1.48 mmol) intoluene (10 mL) was stirred at 90° C. for 16 h. The mixture was filteredthrough celite, H₂O (50 mL) was added, then extracted with EtOAc (50mL×3), combined the organic layers, concentrated to give a residue whichwas purified by flash column (PE/EA=7/3) to afford methyl2,4-dimethyl-5-(1-(2-(trifluoromethoxy)phenyl)piperidin-4-ylamino)benzoate(242 mg, 54.04%) as a pale white solid. ESI-MS (EI+, m/z): 423 [M+H]⁺.

Step 4:2,4-dimethyl-5-(1-(2-(trifluoromethoxy)phenyl)piperidin-4-ylamino)benzoicAcid

2,4-dimethyl-5-[[1-[2-(trifluoromethoxy)phenyl]-4-piperidyl]amino]benzoate(200 mg, 473 umol) in CH₃OH (2 mL) was added LiOH—H₂O (198 mg, 4.73mmol), then the mixture was stirred at 50° C. for 2 h. The solvent wasremoved and quenched with H₂O (10 mL), the pH adjusted to 5-6, extractedwith EtOAc (50 mL×3), concentrated and the crude product was purifiedvia silica gel chromatography eluting with PE/EA from 20/1 to 10/1 toobtain 2,4-dimethyl-5-[[1-[2-(trifluoromethoxy)phenyl]-4-piperidyl]amino]benzoic acid (100 mg, 51.72%) as whitesolid. ESI-MS (EI+, m/z): 409 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.38 (s,1H), 7.24-7.17 (m, 2H), 7.05 (dd, J=8.0, 1.3 Hz, 1H), 7.01-6.96 (m, 2H),3.61-3.50 (m, 1H), 3.41 (d, J=12.2 Hz, 2H), 2.88 (dd, J=16.6, 6.4 Hz,2H), 2.53 (s, 3H), 2.22 (d, J=10.8 Hz, 2H), 2.17 (s, 3H), 1.65 (t,J=13.9, 3.6 Hz, 2H).

Step 5:(S)-(3-((tert-butyldimethylsilyloxy)methyl)-4-(pyridin-2-yl)piperazin-1-yl)(2,4-dimethyl-5-(1-(2-(trifluoromethoxy)phenyl)piperidin-4-ylamino)phenyl)methanone

A mixture of2,4-dimethyl-5-[[1-[2-(trifluoromethoxy)phenyl]-4-piperidyl]amino]benzoic acid (60 mg, 146 umol),tert-butyl-dimethyl-[2-[(2R)-1-(2-pyridyl)piperazin-2-yl]ethoxy] silane(47 mg, 146 umol), HOBT (29 mg, 220 umol), EDCI (43 mg, 220 umol), DIPEA(47 mg, 367 umol) in DMF (3 mL) was stirred at 25° C. for 16 h. Themixture was washed with H₂O (20 mL), extracted with EtOAc (50 mL×3),dried and concentrated to obtain [(3S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(2-pyridyl)piperazin-1-yl]-[2,4-dimethyl-5-[[1-[2-(trifluoromethoxy)phenyl]-4-piperidyl]amino]phenyl]methanone(85 mg, 82.90%) as white solid. ESI-MS (EI+, m/z): 698 [M+H]⁺.

Step 6:(S)-(2,4-dimethyl-5-(1-(2-(trifluoromethoxy)phenyl)piperidin-4-ylamino)phenyl)(3-(hydroxymethyl)-4-(pyridin-2-yl)piperazin-1-yl)methanone

[(3S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(2-pyridyl)piperazin-1-yl]-[2,4-dimethyl-5-[[1-[2-(trifluoromethoxy)phenyl]-4-piperidyl]amino]phenyl]methanone(86 mg, 123 umol), 3HF-TEA (246 umol, 500 uL) in THF (2 mL) was stirredat 25° C. for 2 h. Further purification by preparative HPLC provided[2,4-dimethyl-5-[[1-[2-(trifluoromethoxy)phenyl]-4-piperidyl]amino]phenyl]-[(3S)-3-(hydroxymethyl)-4-(2-pyridyl)piperazin-1-yl]methanone(34 mg, 47.27%) as a white solid. ESI-MS (EI+, m/z): 584 [M+H]⁺. ¹H NMR(500 MHz, MeOD) δ 8.10 (d, J=3.8 Hz, 1H), 7.62-7.53 (m, 1H), 7.28 (t,J=7.7 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.04 (t,J=7.2 Hz, 1H), 6.97 (s, 1H), 6.88-6.81 (m, 1H), 6.72-6.66 (m, 1H),6.65-6.45 (m, 1H), 4.66 (d, J=97.2 Hz, 1H), 4.50-3.98 (m, 2H), 3.59 (m,8H), 3.14 (s, 1H), 2.86 (d, J=10.7 Hz, 2H), 2.31-2.06 (m, 8H), 1.71 (d,J=9.7 Hz, 2H)

Example 142:(S)-(5-(1-(2-(difluoromethoxy)phenyl)piperidin-4-ylamino)-2,4-dimethylphenyl)(3-(hydroxymethyl)-4-(pyridin-2-yl)piperazin-1-yl)methanone,I-184

Synthetic Scheme:

Procedures and Characterization:

Step 1: tert-butyl 1-(2-(difluoromethoxy)phenyl)piperidin-4-ylcarbamate

1-(difluoromethoxy)-2-iodo-benzene (2.7 g, 9.99 mmol), tert-butylN-(4-piperidyl) carbamate (2 g, 9.99 mmol), Pd₂(dba)₃ (540 mg, 600umol), BINAP (740 mg, 1.19 mmol), t-BuONa (1.91 g, 20 mmol) in toluene(50 mL) was stirred at 90° C. for 16 h. The mixture was cooled to rt,quenched with H₂O (100 mL), then extracted with EtOAc (50 mL×3), washedwith brine (50 mL×3), dried, concentrated and purified via silica gelchromatography eluting with PE/EA from 20/1 to 1/1 to afford methyltert-butyl 1-(2-(difluoromethoxy)phenyl)piperidin-4-ylcarbamate (686 mg,20%) as brown solid. MS (EI+, m/z): 343 [M+H]⁺.

Step 2: 1-(2-(difluoromethoxy)phenyl)piperidin-4-amine

A mixture of tert-butylN-[1-[2-(difluoromethoxy)phenyl]-4-piperidyl]carbamate (500 mg, 1.46mmol) in HCl in dioxane (4M, 20 mmol, 5 mL) was stirred at 25° C. for 2h then quenched with water (50 mL), extracted with EtOAc (50 mL×3),adjusted the pH to 8-9, extracted with CH₂Cl₂/CH₃OH=10/1 (50 mL×3),dried and concentrated to obtain1-[2-(trifluoromethoxy)phenyl]piperidin-4-amine (295 mg, 83%). ESI-MS(EI+, m/z): 243 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.20-7.14 (m, 1H),7.10 (d, J=7.1 Hz, 1H), 7.04-6.95 (m, 2H), 6.61 (t, J=76.1 Hz, 1H), 3.39(d, J=12.1 Hz, 2H), 2.81 (d, J=10.3 Hz, 1H), 2.69 (dd, J=16.8, 6.6 Hz,2H), 1.93 (d, J=12.0 Hz, 2H), 1.54-1.46 (m, 3H).

Step 3: methyl5-(1-(2-(difluoromethoxy)phenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate

1-[2-(difluoromethoxy)phenyl]piperidin-4-amine (240 mg, 990 umol),methyl 5-bromo-2,4-dimethyl-benzoate (240 mg, 990 umol), Pd₂(dba)₃ (54mg, 59 umol), BrettPhos (73 mg, 118 umol), Cs₂CO₃ (450 mg, 1 mmol) intoluene (5 mL) was stirred at 90° C. for 16 h. The mixture was filteredby celite, the filtrate was concentrated and was purified via silica gelchromatography eluting with PE/EA from 50/1 to 20/1 to obtain methyl5-[[1-[2-(difluoromethoxy)phenyl]-4-piperidyl]amino]-2,4-dimethyl-benzoate(200 mg, 50%) as white solid. ESI-MS (EI+, m/z): 405 [M+H]⁺.

Step 4:5-(1-(2-(difluoromethoxy)phenyl)piperidin-4-ylamino)-2,4-dimethylbenzoicAcid

To methyl5-[[1-[2-(difluoromethoxy)phenyl]-4-piperidyl]amino]-2,4-dimethyl-benzoate(200 mg, 494 umol) in CH₃OH (5 mL) was added LiOH—H₂O (207 mg, 4 mmol),then the mixture was stirred at 50° C. for 3 h. The pH was adjusted to5-6, then extracted with EtOAc (50 mL×3), washed with brine (50 mL),dried over Na₂SO₄ and concentrated to obtain5-[[1-[2-(difluoromethoxy)phenyl]-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (120 mg, 62%) as yellow solid. ESI-MS (EI+, m/z): 391 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.37 (s, 1H), 7.19 (td, J=7.8, 1.5 Hz, 1H), 7.12(d, J=7.0 Hz, 1H), 7.07-6.96 (m, 3H), 6.62 (t, J=75.8 Hz, 1H), 3.60-3.51(m, 1H), 3.43 (d, J=12.2 Hz, 2H), 2.87 (t, J=10.6 Hz, 2H), 2.53 (s, 3H),2.24 (d, J=12.2 Hz, 2H), 2.18 (s, 3H), 1.64 (t, J=13.8, 3.6 Hz, 2H).

Step 5:(S)-(3-((tert-butyldimethylsilyloxy)methyl)-4-(pyridin-2-yl)piperazin-1-yl)(5-(1-(2-(difluoromethoxy)phenyl)piperidin-4-ylamino)-2,4-dimethylphenyl)methanone

A mixture of5-[[1-[2-(difluoromethoxy)phenyl]-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (60 mg, 153 umol),tert-butyl-dimethyl-[(2R)-1-(2-pyridyl)piperazin-2-yl]oxy-silane (45 mg,153 umol), HOBT (31 mg, 230 umol), EDCI (45 mg, 230 umol), DIPEA (49 mg,384 umol) in DMF (3 mL) was stirred at 25° C. for 16 h. The reactionmixture was quenched with H₂O (10 mL), extracted with EtOAc (50 mL×3),dried and concentrated to obtain(S)-(3-((tert-butyldimethylsilyloxy)methyl)-4-(pyridin-2-yl)piperazin-1-yl)(5-(1-(2-(difluoromethoxy)phenyl)piperidin-4-ylamino)-2,4-dimethylphenyl)methanone (96 mg, 94%) aswhite solid. ESI-MS (EI+, m/z): 666 [M+H]⁺.

Step 6:(S)-(5-(1-(2-(difluoromethoxy)phenyl)piperidin-4-ylamino)-2,4-dimethylphenyl)(3-(hydroxymethyl)-4-(pyridin-2-yl)piperazin-1-yl)methanone

[(3S)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(2-pyridyl)piperazin-1-yl]-[5-[[1-[2-(difluoromethoxy)phenyl]-4-piperidyl]amino]-2,4-dimethyl-phenyl]methanone(92 mg, 135 umol), 3HF-TEA (270 umol, 500 uL) in THF (2 mL) was stirredat 25° C. for 2 h. The mixture was then purifies by preparative HPLC toobtain[5-[[1-[2-(difluoromethoxy)phenyl]-4-piperidyl]amino]-2,4-dimethyl-phenyl]-[(3S)-3-(hydroxymethyl)-4-(2-pyridyl)piperazin-1-yl]methanone(36 mg, 47%) as white solid. ESI-MS (EI+, m/z): 566 [M+H]⁺. ¹H NMR (500MHz, MeOD) δ 8.10 (d, J=3.9 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.21 (t,J=7.4 Hz, 1H), 7.15 (d, J=7.7 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H), 7.02 (t,J=7.4 Hz, 1H), 6.97 (d, J=10.0 Hz, 1H), 6.86 (dd, J=8.5, 5.1 Hz, 1H),6.68 (dd, J=14.5, 9.1 Hz, 1H), 6.63-6.45 (m, 1H), 4.66 (d, J=92.3 Hz,1H), 4.36 (d, J=56.0 Hz, 1H), 4.09 (dd, J=58.9, 13.0 Hz, 1H), 3.85-3.39(m, 8H), 3.13 (d, J=14.9 Hz, 1H), 2.87 (d, J=31.9 Hz, 2H), 2.31-2.04 (m,8H), 1.72 (d, J=10.4 Hz, 2H).

Example 143:3-(4-(3-(1-(3-chloropyridin-2-yl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-2-sulfonamide, I-185

Synthetic Scheme:

Procedures and Characterization:

Step 1:3-(4-(3-(1-(3-chloropyridin-2-yl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-2-sulfonamide

A mixture of3-[[1-(3-chloro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (92 mg, 247 umol), HOBT (50 mg, 371 umol), EDCI (73 mg, 371 umol),DIPEA (80 mg, 619 umol, 108 uL) in DMF (3 mL) was stirred at 25° C. for1 h, then 3-piperazin-1-ylpyridine-2-sulfonamide (60 mg, 247 umol) wasadded and stirred at 25° C. for another 16 h. The mixture was quenchedwith H₂O (6 mL), extracted with EtOAc (50 mL×3) and the crude productwas purified by Pre-HPLC to obtain3-[4-[3-[[1-(3-chloro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]piperazin-1-yl]pyridine-2-sulfonamide(27 mg, 18%) as white solid. MS (EI+, m/z): 599 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d6) δ 8.37 (d, J=4.5 Hz, 1H), 8.19 (d, J=4.7 Hz, 1H), 7.92 (d,J=8.2 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.61 (dd, J=8.1, 4.5 Hz, 1H),7.20 (s, 2H), 6.96 (dd, J=7.7, 4.7 Hz, 1H), 6.86 (s, 1H), 3.84 (d,J=19.5 Hz, 2H), 3.71 (d, J=12.0 Hz, 3H), 3.24 (s, 2H), 3.09 (dd, J=17.2,9.2 Hz, 2H), 2.92 (s, 3H), 2.77 (dd, J=19.6, 11.6 Hz, 2H), 2.23 (s, 3H),2.11 (d, J=14.8 Hz, 6H), 1.84 (s, 2H), 1.63 (dd, J=23.5, 12.0 Hz, 2H).

Example 144:2-(4-(3-(1-(3-chloropyridin-2-yl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide,I-186

Synthetic Scheme:

Procedures and Characterization:

Step 1:2-(4-(3-(1-(3-chloropyridin-2-yl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide

3-[[1-(3-chloro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (92 mg, 247 umol), HOBT (50 mg, 371 umol), EDCI (73 mg, 371 umol),DIPEA (80 mg, 619 umol, 108 uL) in DMF (3 mL) was stirred at 25° C. for1 h, then 2-piperazin-1-ylpyridine-3-sulfonamide (60 mg, 247 umol) wasadded and stirred at 25° C. for another 16 h. The mixture was quenchedwith H₂O (6 mL), extracted with EtOAc (50 mL×3) and the crude productwas purified via preparative HPLC to obtain2-[4-[3-[[1-(3-chloro-2-pyridyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylpiperazin-1-yl]pyridine-3-sulfonamide (38 mg, 26%) as white solid. MS(EI+, m/z): 599 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d6) δ 8.50 (dd, J=4.7, 1.6Hz, 1H), 8.23 (dd, J=7.8, 1.6 Hz, 1H), 8.20-8.17 (m, 1H), 7.77 (d, J=7.7Hz, 1H), 7.32 (s, 2H), 7.29 (dd, J=7.8, 4.8 Hz, 1H), 6.96 (dd, J=7.7,4.7 Hz, 1H), 6.86 (s, 1H), 3.90 (d, J=18.1 Hz, 2H), 3.71 (d, J=12.1 Hz,3H), 3.24 (d, J=4.5 Hz, 4H), 3.10 (s, 2H), 2.93 (s, 1H), 2.76 (dd,J=20.2, 11.0 Hz, 2H), 2.23 (s, 3H), 2.10 (d, J=16.2 Hz, 6H), 1.85 (s,2H), 1.73-1.57 (m, 2H).

Example 145:2-(4-(5-(1-(2-cyano-4,6-difluorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)-6-fluorobenzenesulfonamide,I-187

Synthetic Scheme:

Procedures and Characterization:

Step 1: 2-amino-3,5-difluorobenzonitrile

A mixture of 2-bromo-4,6-difluoro-aniline (2 g, 9 mmol), CuCN (2.34 g,25 mmol) in NMP (5 mL) was stirred at 140° C. for 16 h. The reaction wasmonitored by TLC (PE/EA=30/1), then eluted with EtOAc (50 mL×3), asolution of FeCl₃ in HCl was added and extracted. This was then purifiedby SGC eluting with PE/EA from 30/1 to obtain2-amino-3,5-difluoro-benzonitrile (1.02 g, 69%) as yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 7.02 (m, 1H), 6.95 (m, 1H), 4.38 (s, 2H).

Step 2: 2-(4-aminopiperidin-1-yl)-3,5-difluorobenzonitrile

2-amino-3,5-difluoro-benzonitrile (800 mg, 5.19 mmol),1,5-dibromopentan-3-amine (2.54 g, 7.79 mmol) in n-BuOH (3 mL) wasstirred at 120° C. for 16 h. This was then purified by SGC(DCM/MeOH=20/1) to obtain2-(4-amino-1-piperidyl)-3,5-difluoro-benzonitrile (500 mg, 41%) asyellow solid. ESI-MS (EI+, m/z): 238 [M+H]⁺.

Step 3: methyl5-(1-(2-cyano-4,6-difluorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoate

A solution of 2-(4-amino-1-piperidyl)-3,5-difluoro-benzonitrile (120 mg,505 umol), methyl 5-bromo-2,4-dimethyl-benzoate (122 mg, 505 umol),Pd₂(dba)₃ (27 mg, 30 umol), BrettPhos (37 mg, 60 umol), Cs₂CO₃ (230 mg,708 umol) in toluene (5 mL) was stirred at 100° C. for 16 h. Filteredand concentrated, the crude product was purified via silica gelchromatography to obtain methyl5-[[1-(2-cyano-4,6-difluoro-phenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate(80 mg, 40%) as yellow solid. ESI-MS (EI+, m/z): 400 [M+H]⁺.

Step 4:5-(1-(2-cyano-4,6-difluorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoicAcid

A solution of methyl5-[[1-(2-cyano-4,6-difluoro-phenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoate(70 mg, 175 umol), LiOH (33 mg, 1.4 mmol) in CH₃OH (5 mL) and H₂O (3 mL)was stirred at 25° C. for 4 h then extracted with DCM (20 mL), adjustedto pH5-6, extracted with DCM/CH₃OH (50 mL×3), dried and concentrated toobtain the5-[[1-(2-cyano-4,6-difluoro-phenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (50 mg, 74%). ESI-MS (EI+, m/z): 386 [M+H]⁺.

Step 5:2-(4-(5-(1-(2-cyano-4,6-difluorophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)piperazin-1-yl)-6-fluorobenzenesulfonamide

5-[[1-(2-cyano-4,6-difluoro-phenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoicacid (40 mg, 103 umol), 2-fluoro-6-piperazin-1-yl-benzenesulfonamide (34mg, 134 umol), HOBT (21 mg, 155 umol), EDC (29 mg, 155 umol), DIPEA (33mg, 259 umol) in DMF (3 mL) was stirred at 25° C. for 16 h. Theresulting material was purified via preparative HPLC to obtain2-[4-[5-[[1-(2-cyano-4,6-difluoro-phenyl)-4-piperidyl]amino]-2,4-dimethyl-benzoyl]piperazin-1-yl]-6-fluoro-benzenesulfonamide(3 mg, 5%). ESI-MS (EI+, m/z): 627 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 7.58(dd, J=14.2, 8.2 Hz, 1H), 7.42-7.24 (m, 1H), 7.15-7.02 (m, 1H), 6.97 (s,1H), 6.57 (s, 1H), 3.54 (dd, J=12.1, 7.8 Hz, 1H), 3.36 (s, 1H),3.22-2.86 (m, 1H), 2.26-1.98 (m, 2H), 1.73 (d, J=7.4 Hz, 1H), 1.32 (s,1H).

Example 146:(S)-2-(4-(3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)-3-methylpiperazin-1-yl)pyridine-3-sulfonamide, I-188

Procedures and Characterization:

Step 1: (S)-2-(3-methylpiperazin-1-yl)pyridine-3-sulfonamide

To a mixture of (S)-2-methylpiperazine (7.99 g, 79.74 mmol), K₂CO₃ (8.25g, 59 mmol) in dioxane (5 mL) was added 2-chloropyridine-3-sulfonamide(3.84 g, 19.94 mmol) in three portions every 30 min at 80° C., thenstirred at 80° C. for 30 min. The reaction mixture was concentrated andwashed with CH₃CN (50 mL×3) to obtain the crude product2-[(3S)-3-methylpiperazin-1-yl]pyridine-3-sulfonamide (4.85 g, 95%) asyellow solid and used in the next step without further purification. MS(EI+, m/z): 257 [M+H]⁺.

Step 2: (S)-tert-butyl2-methyl-4-(3-sulfamoylpyridin-2-yl)piperazine-1-carboxylate

To a mixture of 2-[(3S)-3-methylpiperazin-1-yl]pyridine-3-sulfonamide(4.8 g, 18.73 mmol) in CH₃CN (70 mL) was added a solution oftert-butoxycarbonyl tert-butyl carbonate (16.35 g, 74.91 mmol) in H₂O(50 mL), then the mixture stirred at 25° C. for 17 h. The reactionmixture was concentrated and extracted with EtOAc (50 mL×3), dried andconcentrated. The crude product was purified via silica gelchromatography eluting with PE/EA from 20/1 to 50/1 to obtain tert-butyl(2S)-2-methyl-4-(3-sulfamoyl-2-pyridyl)piperazine-1-carboxylate (5.3 g,79%) as off-white solid. MS (EI+, m/z): 357 [M+H]⁺.

Step 3: (S)-2-(3-methylpiperazin-1-yl)pyridine-3-sulfonamide

A solution of tert-butyl(2S)-2-methyl-4-(3-sulfamoyl-2-pyridyl)piperazine-1-carboxylate (5.20 g,14.59 mmol) in HCl in dioxane (4 M, 72.94 mmol, 19 mL) was stirred at25° C. for 1 h. The reaction mixture was filtered, the crude product waswashed with Et₂O (50 mL×3) and CH₃CN (50 mL×3), dried to obtain2-[(3S)-3-methylpiperazin-1-yl]pyridine-3-sulfonamide (3.20 g, 75%) aswhite solid. MS (EI+, m/z): 257 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.97(d, J=9.3 Hz, 1H), 9.47 (d, J=7.9 Hz, 1H), 8.84 (s, 2H), 8.52 (dd,J=4.8, 1.8 Hz, 1H), 8.28 (dd, J=7.8, 1.8 Hz, 1H), 7.74-7.41 (m, 1H),7.34 (dd, J=7.8, 4.8 Hz, 1H), 3.58 (t, J=11.1 Hz, 3H), 3.41-3.20 (m,3H), 3.13-2.99 (m, 1H), 1.29 (d, J=6.5 Hz, 3H).

Step 4:(S)-2-(4-(3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)-3-methylpiperazin-1-yl)pyridine-3-sulfonamide

To a solution of3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoic acid(297 mg, 819 umol) in DCM (5 mL) was added SOCl₂ (0.5 mL) and themixture stirred at 20° C. for 2 h. The mixture was concentrated toobtain 3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (260 mg, 99.67%) as a yellow solid which was used directly. ACH₃CN solution (5 mL) containing(S)-2-(3-methylpiperazin-1-yl)pyridine-3-sulfonamide (160 mg, 546 umol),TEA (105 mg, 1.04 umol) was added in3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (250 mg, 655 umol), then the mixture was stirred at 20° C. for2 h, quenched with water (30 mL), extracted with EtOAc (50 mL×3), driedand concentrated. The crude product was purified via silica gelchromatography eluting with DCM/MeOH from 50/1 to 30/1 to obtain2-[(3S)-4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]pyridine-3-sulfonamide(54 mg, 16%) as yellow solid. MS (EI+, m/z): 602 [M+H]J. ¹H NMR (500MHz, MeOD) δ 8.41-8.36 (m, 1H), 8.24-8.18 (m, 1H), 7.49 (d, J=7.6 Hz,1H), 7.46-7.39 (m, 1H), 7.15 (m, 1H), 7.05 (d, J=8.2 Hz, 1H), 6.94 (dd,J=8.6, 6.5 Hz, 1H), 6.85 (dd, J=12.5, 5.7 Hz, 1H), 4.94 (s, 1H),3.71-3.31 (m, 6H), 3.16-3.02 (m, 2H), 3.01-2.82 (m, 2H), 2.81-2.67 (m,2H), 2.26-2.01 (m, 9H), 1.90 (s, 2H), 1.66 (d, J=8.2 Hz, 2H), 1.40 (t,J=6.4 Hz, 2H), 1.25 (d, J=6.7 Hz, 1H).

Example 147:2-(4-(3-((S)-4-(3-fluoro-2-((S)-S-methylsulfonimidoyl)phenyl)-2-methylpiperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)benzonitrile,I-189

Procedures and Characterization:

Step 1: tert-butylN-[[2-fluoro-6-[(3S)-3-methylpiperazin-1-yl]phenyl]-(S)-methyl-6-sulfanylidene]carbamate

A mixture of tert-butylN-[(2,6-difluorophenyl)-methyl-6-sulfanylidene]carbamate (2.10 g, 7.21mmol), (2S)-2-methylpiperazine (722 mg, 7.21 mmol), K₂CO₃ (1.99 g, 14.42mmol) and DMF (2 mL) was stirred at 110° C. for 1 h. The reactionmixture was quenched with water (50 mL), extracted with EtOAc (50 mL×3),dried and concentrated. The crude product was purified via silica gelchromatography eluting with DCM/MeOH from 40/1 to 10/1 to obtain totalproduct 2.1 g, further purification was carried on chiral-HPLC to obtaintert-butylN-[[2-fluoro-6-[(3S)-3-methylpiperazin-1-yl]phenyl]-methyl-6-sulfanylidene]carbamate(840 mg, 31%) as colorless gum. MS (EI+, m/z): 372 [M+H]⁺.

Step 2:N-[[2-[(3S)-4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-(S)-methyl-oxo-6-sulfanylidene]carbamate

To a solution of3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoic acid(297 mg, 819 umol) in DCM (5 mL) was added SOCl₂ (0.5 mL) and stirred at20° C. for 2 h. The mixture was concentrated to obtain3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (260 mg, 680 umol, 99.67%) as a yellow solid, which used in thenext step without further purification. To a mixture of tert-butylN-[[2-fluoro-6-[(3S)-3-methylpiperazin-1-yl]phenyl]-methyl-6-sulfanylidene]carbamate(258 mg, 694 umol) and TEA (84 mg, 833 umol) in CH₃CN (5 mL) was addedin 3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (260 mg, 680 umol), then the mixture was stirred at 20° C. for48 h, quenched with water (30 mL), extracted with EtOAc (50 mL×3), driedand concentrated, the crude product was purified via silica gelchromatography eluting with PE/EA from 6/1 to 3/1 to obtain tert-butylN-[[2-[(3S)-4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-methyl-oxo-6-sulfanylidene]carbamate(260 mg, 52%) as colorless gum. MS (EI+, m/z): 717 [M+H]⁺.

Step 3:2-(4-(3-((S)-4-(3-fluoro-2-((S)-S-methylsulfonimidoyl)phenyl)-2-methylpiperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)benzonitrile

To a solution of tert-butylN-[[2-[(3S)-4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-methyl-6-sulfanylidene]carbamate(240 mg, 334 umol) in DCM (7 mL) was added TFA (3 mL), then the mixturewas stirred at 20° C. for 2 h, concentrated and adjusted to pH 7-8 withNEt₃ (3 mL), concentrated and purified by preparative HPLC to obtain2-[4-[3-[(2S)-4-[3-fluoro-2-(methylsulfonimidoyl)phenyl]-2-methyl-piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]benzonitrile(48 mg, 23%) as white solid. MS (EI+, m/z): 617 [M+H]⁺. ¹H NMR (500 MHz,MeOD) δ 7.63 (dd, J=18.4, 8.0 Hz, 2H), 7.56 (t, J=7.9 Hz, 1H), 7.38 (dd,J=15.5, 8.1 Hz, 1H), 7.18 (t, J=9.7 Hz, 2H), 7.07 (t, J=7.5 Hz, 1H),6.97 (d, J=16.7 Hz, 1H), 5.11 (s, 1H), 3.88-3.44 (m, 7H), 3.31-3.01 (m,4H), 2.81 (dd, J=56.4, 44.4 Hz, 3H), 2.38-2.29 (m, 4H), 2.29-2.17 (m,5H), 2.02 (d, J=11.0 Hz, 2H), 1.78 (d, J=12.1 Hz, 2H), 1.56 (d, J=6.9Hz, 2H), 1.40 (d, J=6.8 Hz, 1H).

Example 148:2-(4-(3-((S)-4-(3-fluoro-2-((R)-S-methylsulfonimidoyl)phenyl)-2-methylpiperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)benzonitrile,I-190

Procedures and Characterization:

Step 1: tert-butylN-[[2-fluoro-6-[(3S)-3-methylpiperazin-1-yl]phenyl]-(R)-methyl-6-sulfanylidene]carbamate

A mixture of tert-butylN-[(2,6-difluorophenyl)-methyl-6-sulfanylidene]carbamate (2.10 g, 7.21mmol), (2S)-2-methylpiperazine (722 mg, 7.21 mmol), K₂CO₃ (1.99 g, 14.42mmol) in DMF (2 mL) was stirred at 110° C. for 1 h. The reaction mixturewas quenched with water (50 mL), extracted with EtOAc (50 mL×3), driedand concentrated, the crude product was purified via silica gelchromatography eluting with DCM/MeOH from 40/1 to 10/1 to obtain totalproduct 2.1 g, further purification was carried out via chiral-HPLC toobtain tert-butylN-[[2-fluoro-6-[(3S)-3-methylpiperazin-1-yl]phenyl]-(R)-methyl-6-sulfanylidene]carbamate(710 mg, 27%) as colorless gum. MS (EI+, m/z): 372 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 7.48 (m, 1H), 7.09 (dd, J=8.1, 3.7 Hz, 1H), 6.99-6.90 (m,1H), 3.51 (d, J=17.8 Hz, 1H), 3.21-2.71 (m, 2H), 2.37 (dt, J=41.8, 10.4Hz, 1H), 1.36 (s, 3H), 1.02 (d, J=6.3 Hz, 1H).

Step 2:N-[[2-[(3S)-4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-(R)-methyl-oxo-6-sulfanylidene]carbamate

To a solution of3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoic acid(400 mg, 1.1 mmol) in DCM (10 mL) was added SOCl₂ (0.2 mL), then themixture stirred at 20° C. for 2 h. The mixture was concentrated toobtain 3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (420 mg, 90.44%) as yellow solid, which was used in the nextstep without further purification. To a solution of tert-butylN-[[2-fluoro-6-[(3S)-3-methylpiperazin-1-yl]phenyl]-(R)-methyl-6-sulfanylidene]carbamate(320 mg, 861 umol), NEt₃ (104 mg, 1.03 mmol) in CH₃CN (5 mL) was added3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (394 mg, 1.03 mmol), then the reaction mixture was stirred at30° C. for 48 h. Quenched with water (30 mL), extracted with EtOAc (50mL×3), dried and concentrated, the crude product was purified via silicagel chromatography eluting with DCM/CH₃OH from 30/1 to 10/1 to obtaintert-butylN-[[2-[(3S)-4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-(R)-methyl-6-sulfanylidene]carbamate(240 mg, 39%) as yellow solid. MS (EI+, m/z): 717 [M+H]⁺.

Step 3:2-(4-(3-((S)-4-(3-fluoro-2-((R)-S-methylsulfonimidoyl)phenyl)-2-methylpiperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)benzonitrile

To a solution of tert-butylN-[[2-[(3S)-4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-(R)-methyl-6-sulfanylidene]carbamate(220 mg, 306 umol) in DCM (7 mL) was added TFA (3 mL), then the mixturewas stirred at 20° C. for 2 h. Concentrated and adjusted the pH to 7˜8with NEt₃ (3 mL), concentrated and purified by Pre-HPLC to obtain2-[4-[3-[(2S)-4-[3-fluoro-2-(methylsulfonimidoyl)phenyl]-2-methyl-piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]benzonitrile(73 mg, 39%) as white solid. MS (EI+, m/z): 617 [M+H]⁺. ¹H NMR (500 MHz,MeOD) δ 7.67-7.58 (m, 1H), 7.57-7.51 (m, 1H), 7.34 (dd, J=10.9, 5.9 Hz,1H), 7.15 (dd, J=16.8, 8.6 Hz, 1H), 7.06 (td, J=7.5, 2.6 Hz, 1H), 6.97(dd, J=15.8, 5.0 Hz, 1H), 5.07 (s, 1H), 2.37-2.14 (m, 1H), 2.07-1.95 (m,1H), 1.78 (dd, J=23.2, 11.5 Hz, 1H), 1.55 (t, J=6.5 Hz, 1H), 1.39 (dt,J=38.8, 19.4 Hz, 1H).

Example 149:5-fluoro-2-(4-(3-((2S)-4-(3-fluoro-2-(S-methylsulfonimidoyl)phenyl)-2-methylpiperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)benzonitrile,I-191

Synthetic Scheme:

Procedures and Characterization:

Step 1: tert-butylN-[[2-[(3S)-4-[3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-(S)-methyl-6-sulfanylidene]carbamate

To a solution of3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (500 mg, 1.31 mmol) in DCM (20 mL) was added SOCl₂ (311 mg, 2.62mmol), then the mixture was stirred at 20° C. for 1 h. The mixture wasconcentrated, the crude product3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (520 mg, 1.30 mmol, 99.20%) was used in the next step withoutfurther purification. A mixture of tert-butylN-[[2-fluoro-6-[(3S)-3-methylpiperazin-1-yl]phenyl]-(S)-methyl-6-sulfanylidene]carbamate(268 mg, 722 umol) in CH₃CN (20 mL) was added TEA (87 mg, 866 umol), and3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (520 mg, 1.30 mmol), then the mixture stirred at 20° C. for 8h. Quenched with water (30 mL), extracted with EtOAc (50 mL×3), driedand concentrated, the crude product was purified via silica gelchromatography eluting with DCM/CH₃OH from 50/1 to 30/1 to obtaintert-butylN-[[2-[(3S)-4-[3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-(S)-methyl-6-sulfanylidene]carbamate(260 mg, 49%) as yellow solid. MS (EI+, m/z): 735 [M+H]⁺.

Step 2:5-fluoro-2-(4-(3-((2S)-4-(3-fluoro-2-(S-methylsulfonimidoyl)phenyl)-2-methylpiperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)benzonitrile

To a solution of tert-butylN-[[2-[(3S)-4-[3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-(S)-methyl-6-sulfanylidene]carbamate(240 mg, 326 umol) in DCM (10 mL) was added in TFA (10 mL), the mixturewas stirred at 20° C. for 2 h. Concentrated and eluted with CH₃CN (3mL), then adjusted the pH to 7-8 with NEt₃, removed the solvent and sentto pre-HPLC to obtain5-fluoro-2-[4-[3-[(2S)-4-[3-fluoro-2-(methylsulfonimidoyl)phenyl]-2-methyl-piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]benzonitrile(96 mg, 46%) as white solid. MS (EI+, m/z): 635 [M+H]⁺. ¹H NMR (500 MHz,MeOD) δ 7.63 (dd, J=14.5, 8.2 Hz, 1H), 7.48-7.29 (m, 3H), 7.23-7.15 (m,2H), 6.97 (d, J=16.7 Hz, 1H), 5.11 (m, 1H), 3.85-3.40 (m, 7H), 3.29-3.01(m, 4H), 2.91-2.58 (m, 3H), 2.37-2.15 (m, 9H), 2.07-1.96 (m, 2H), 1.78(q, J=11.7 Hz, 2H), 1.56 (d, J=6.9 Hz, 2H), 1.39 (d, J=6.8 Hz, 1H).

Example 150:2-(4-(3-((2S)-4-(3-fluoro-2-(S-methylsulfonimidoyl)phenyl)-2-methylpiperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)benzonitrile,I-192

Synthetic Scheme:

Procedures and Characterization:

Step 1: tert-butylN-[[2-[(3S)-4-[3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-(S)-methyl-6-sulfanylidene]carbamate

To a solution of3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (500 mg, 1.31 mmol) in DCM (20 mL) was added SOCl₂(311 mg, 2.62mmol), then the mixture was stirred at 20° C. for 1 h. Concentrated, thecrude product3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (520 mg, 99.20%) was used in the next step without furtherpurification. Tert-butylN-[[2-fluoro-6-[(3S)-3-methylpiperazin-1-yl]phenyl]-(S)-methyl-6-sulfanylidene]carbamate(309 mg, 833 umol) in CH₃CN (20 mL) was added in3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (500 mg, 1.25 mmol) and NEt₃ (126 mg, 1.25 mmol), then themixture was stirred at 20° C. for 16 h. Quenched with water(30 mL),extracted with EtOAc (50 mL×3), dried and concentrated, the crudeproduct was purified via silica gel chromatography eluting withDCM/CH₃OH from 50/1 to 30/1 to obtain tert-butylN-[[2-[(3S)-4-[3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-(S)-methyl-6-sulfanylidene]carbamate(250 mg, 41%) as white solid. MS (EI+, m/z): 735 [M+H]⁺.

Step 2:5-fluoro-2-(4-(3-((2S)-4-(3-fluoro-2-(S-methylsulfonimidoyl)phenyl)-2-methylpiperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)benzonitrile

To tert-butyl N-[[2-[(3S)-4-[3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]-6-fluoro-phenyl]-(S)-methyl-6-sulfanylidene]carbamate (200 mg, 272 umol) in DCM (10 mL) was added TFA (10 mL), thenthe mixture was stirred at 20° C. for 2 h then purified via preparativeHPLC to obtain5-fluoro-2-[4-[3-[(2S)-4-[3-fluoro-2-(methylsulfonimidoyl)phenyl]-2-methyl-piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]benzonitrile(30 mg, 17%) as white solid. MS (EI+, m/z): 635 [M+H]⁺. ¹H NMR (500 MHz,MeOD) δ 7.62 (dd, J=14.6, 8.2 Hz, 1H), 7.43 (dd, J=7.5, 3.8 Hz, 1H),7.34 (dd, J=8.2, 5.5 Hz, 2H), 7.18 (m, 2H), 6.97 (dd, J=15.7, 4.7 Hz,1H), 5.08 (s, 1H), 3.69 (dd, J=35.5, 22.8 Hz, 1H), 3.46 (dd, J=21.9, 6.8Hz, 5H), 3.17 (m, 4H), 2.85 (m, 3H), 2.43-2.10 (m, 9H), 2.00 (t, J=15.7Hz, 2H), 1.86-1.72 (m, 2H), 1.55 (t, J=6.5 Hz, 2H), 1.40 (m, 1H).

Example 151:(S)-2-(4-(3-(1-(2-cyano-4-fluorophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)-3-methylpiperazin-1-yl)pyridine-3-sulfonamide,I-193

Synthetic Scheme:

Procedures and Characterization:

Step 1:(S)-2-(4-(3-(1-(2-cyano-4-fluorophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl-3-methylpiperazin-1-yl)pyridine-3-sulfonamide

To a solution of3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (200 mg, 524 umol) in DCM (5 mL) was added SOCl₂ (0.5 mL) then themixture stirred at 20° C. for 2 h. The mixture was concentrated toobtain3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (209 mg, 99.68%) as yellow solid which was used in the nextstep without further purification.2-[(3S)-3-methylpiperazin-1-yl]pyridine-3-sulfonamide (127 mg, 433umol), NEt₃ (87.79 mg, 867 umol) in CH₃CN (5 mL) was added to3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoylchloride (208 mg, 520 umol) in CH₃CN (5 mL) then the mixture was stirredat 20° C. for 16 h then quenched with water (3 mL). The mixture waspurified via preparative HPLC to obtain2-[(3S)-4-[3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-3-methyl-piperazin-1-yl]pyridine-3-sulfonamide(64 mg, 24%) as a white solid. MS (EI+, m/z): 620. [M+H]⁺. ¹H NMR (500MHz, MeOD) δ 8.51 (t, J=4.7, 1.5 Hz, 1H), 8.33 (t, J=7.8, 1.8 Hz, 1H),7.43 (t, J=8.0, 3.1 Hz, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.24-7.16 (m,1H), 6.97 (dd, J=12.4, 5.8 Hz, 1H), 5.05 (m, 1H), 3.82-3.60 (m, 2H),3.58-3.38 (m, 3H), 3.28-3.15 (m, 2H), 3.14-2.97 (m, 2H), 2.85-2.71 (m,2H), 2.37-2.10 (m, 9H), 2.02 (s, 2H), 1.86-1.71 (m, 2H), 1.59-1.46 (m,2H), 1.37 (dd, J=6.8, 1.8 Hz, 1H).

Example 152:(R)-2-(4-(3-(3-(aminomethyl)-4-(pyridazin-3-yl)piperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)benzonitrile,I-194

Synthetic Scheme:

Procedures and Characterization:

Step 1: (S)-benzyl4-(pyridazin-3-yl)-3-(((2-(trimethylsilyl)ethoxy)carbonylamino)methyl)piperazine-1-carboxylate

A mixture of benzyl(3S)-3-[(2-trimethylsilylethoxycarbonylamino)methyl]piperazine-1-carboxylate(600 mg, 1.52 mmol), 3-bromopyridazine (484 mg, 3.05 mmol), Pd₂(dba)₃(139 mg, 152 umol), t-BuONa (293 mg, 3.05 mmol) in toluene (20 mL) wasstirred at 100° C. for 16 h. Filtered and concentrated, the crudeproduct was purified via silica gel chromatography eluting with PE/EAfrom 100/1 to 1/100 to obtain benzyl(3S)-4-pyridazin-3-yl-3-[(2-trimethylsilylethoxycarbonyl-amino)methyl]piperazine-1-carboxylate(260 mg, 36%) as yellow gum. MS (EI+, m/z): 472 [M+H]⁺.

Step 2: (R)-2-(trimethylsilyl)ethyl(1-(pyridazin-3-yl)piperazin-2-yl)methylcarbamate

benzyl (3S)-4-pyridazin-3-yl-3-[(2-trimethylsilylethoxycarbonylamino)methyl]piperazine-1-carboxylate(250 mg, 530 umol), Pd/C (100 mg, 823 umol), NH₄OH (0.2 mL) in EtOH (5mL) was stirred at 20° C. for 0.5 h. The mixture was filtered andconcentrated to obtain (R)-2-(trimethylsilyl)ethyl(1-(pyridazin-3-yl)piperazin-2-yl)methylcarbamate (178 mg, 99%) asyellow solid. MS (EI+, m/z): 338 [M+H]⁺.

Step 3: (R)-2-(trimethylsilyl)ethyl(4-(3-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)-1-(pyridazin-3-yl)piperazin-2-yl)methylcarbamate

3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoic acid(103 mg, 284 umol), HOBT (41 mg, 308 umol), EDCI (54 mg, 284 umol),DIPEA (153 mg, 1.1 mmol), DMAP (2 mg, 23 umol) in DMF (10 mL) wasstirred at rt for 1 h, 2-trimethylsilylethylN-[[(2S)-1-pyridazin-3-ylpiperazin-2-yl]methyl]carbamate (80 mg, 237umol) was added in and stirred at 35° C. for 16 h. Quenched by H₂O (10mL), extracted with EtOAc (50 mL×3), dried and concentrated, waspurified via preparative HPLC to obtain 2-trimethylsilylethylN-[[(2R)-4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-1-pyridazin-3-yl-piperazin-2-yl]methyl]carbamate(50 mg, 31%) as white solid. MS (EI+, m/z): 683 [M+H]⁺.

Step 4:(R)-2-(4-(3-(3-(aminomethyl)-4-(pyridazin-3-yl)piperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)benzonitrile

2-trimethylsilylethylN-[[(2R)-4-[3-[[1-(2-cyanophenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoyl]-1-pyridazin-3-yl-piperazin-2-yl]methyl]carbamate(40 mg, 58 umol) in THF (3 mL) was added in TBAF in THF (78 mg, 0.3mmol), then the mixture was stirred at 50° C. for 1 h. Quenched with H₂O(30 mL), extracted with EtOAc (50 mL×3), adjusted the pH to 8-9,extracted with EtOAc (50 mL×3), washed with H₂O (50 mL×3), dried andconcentrated, was purified via preparative HPLC to obtain2-[4-[3-[(3R)-3-(aminomethyl)-4-pyridazin-3-yl-piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]benzonitrile(11 mg, 35%) as white solid. MS (EI+, m/z): 539 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.60 (d, J=4.4 Hz, 1H), 7.56 (d, J=6.6 Hz, 1H), 7.47 (t, J=7.9Hz, 1H), 7.24 (dd, J=9.3, 4.5 Hz, 1H), 7.04-6.83 (m, 4H), 5.01-4.62 (m,1H), 4.44 (s, 1H), 4.25 (m, 1H), 3.59 (t, J=17.9 Hz, 3H), 3.48-3.10 (m,3H), 3.10-2.70 (m, 5H), 2.35-2.22 (m, 6H), 2.09 (t, J=40.7, 8.2 Hz, 5H),1.69 (d, J=11.4 Hz, 2H).

Example 153:(R)-2-(4-(3-(3-(aminomethyl)-4-(pyridazin-3-yl)piperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)-5-fluorobenzonitrile,I-195

Synthetic Scheme:

Procedures and Characterization:

Step 1: (R)-2-(trimethylsilyl)ethyl(4-(3-(1-(2-cyano-4-fluorophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)-1-(pyridazin-3-yl)piperazin-2-yl)methylcarbamate

A mixture of3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino]-2,4,6-trimethyl-benzoicacid (108 mg, 284 umol), HOBT (41 mg, 308 umol), EDCI (54 mg, 284 umol),DIPEA (153 mg, 1.19 mmol), DMAP (2 mg, 23 umol) in DMF (10 mL) wasstirred at rt for 1 h, 2-trimethylsilylethylN-[[(2S)-1-pyridazin-3-ylpiperazin-2-yl]methyl]carbamate (80 mg, 237umol) was added in and stirred at 35° C. for 16 h. The reaction wasquenched with H₂O (10 mL), extracted with EtOAc (50 mL×3), dried andconcentrated and purified via preparative HPLC to obtain(R)-2-(trimethylsilyl)ethyl(4-(3-(1-(2-cyano-4-fluorophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)-1-(pyridazin-3-yl)piperazin-2-yl)methylcarbamate(50 mg, 30%) as a white solid. MS (EI+, m/z): 701 [M+H]⁺.

Step 2:(R)-2-(4-(3-(3-(aminomethyl)-4-(pyridazin-3-yl)piperazine-1-carbonyl)-2,4,6-trimethylphenylamino)piperidin-1-yl)-5-fluorobenzonitrile

2-trimethylsilylethylN-[[(2R)-4-[3-[[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]amino-2,4,6-trimethyl-benzoyl]-1-pyridazin-3-yl-piperazin-2-yl]methyl]carbamate(50 mg, 71 umol) in THF (3 mL) was added to TBAF in THF (18 mg, 71umol), then the mixture was stirred at 50° C. for 1 h. The mixture wasquenched with water (30 mL), extracted with EtOAc (50 mL×3), adjustedthe pH to 8˜9, extracted with EtOAc (50 mL×3), washed with H₂O (50mL×3), dried and concentrated and purified via preparative HPLC toobtain 2-[4-[3-[(3R)-3-(aminomethyl)-4-pyridazin-3-yl-piperazine-1-carbonyl]-2,4,6-trimethyl-anilino]-1-piperidyl]-5-fluoro-benzonitrile(30 mg, 76%) as white solid. MS (EI+, m/z): 557 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.61-8.57 (m, 1H), 7.21-7.12 (m, 3H), 7.07-6.85 (m, 3H),5.03-4.57 (m, 1H), 4.43 (s, 1H), 4.25 (dd, J=56.2, 13.0 Hz, 1H),3.67-3.29 (m, 4H), 3.28-2.88 (m, 5H), 2.85-2.65 (m, 2H), 2.34-2.18 (m,6H), 2.08 (t, J=43.3, 8.2 Hz, 5H), 1.69 (dd, J=23.8, 11.9 Hz, 2H).

Amide Coupling Using HATU: Generic Method

Example 154:2-[4-({5-[4-(2-Cyanophenyl)piperazine-1-carbonyl]-2,4-dimethylphenyl}amino)piperidin-1-yl]benzonitrile,I-71

To a suspension of5-{[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid[Intermediate 1] (30 mg, 0.085 mmol) and HATU (36 mg, 0.094 mmol) in DMF(1 ml) was added DIPEA (46 μl, 0.256 mmol) and the resultant solutionwas stirred at rt for 1 h. 2-(Piperazin-1-yl)benzonitrile (16 mg, 0.085mmol) was then added and the reaction was stirred at rt for 18 h. Thereaction was purified by preparative HPLC (Generic UV-Directed High pHprep method). The fractions containing product were lyophilized toafford the title compound I-71 as a white solid (13 mg, 29%). ¹H NMR(500 MHz, Chloroform-d) δ 7.63-7.53 (m, 2H), 7.53-7.46 (m, 2H),7.09-6.98 (m, 4H), 6.92 (s, 1H), 6.48 (s, 1H), 4.14-3.93 (m, 2H),3.67-3.58 (m, 1H), 3.57-3.45 (m, 4H), 3.45-3.31 (m, 1H), 3.32-3.19 (m,2H), 3.14-3.06 (m, 2H), 3.03-2.90 (m, 2H), 2.30-2.18 (m, 5H), 2.13 (s,3H), 1.84-1.73 (m, 1H), 1.72-1.63 (m, 1H). LCMS Method 7—Tr=4.09 min(ES+) (M+H)+ 519

Additional, nonlimiting examples of the general HATU coupling method areexemplified in Table 13 below. Intermediate Acid (1 eq) and HATU(1.1-1.4 eq) were dissolved in DMF. DiPEA (3-5 eq) was added and thereaction mixture stirred at ambient temperature for 30 mins.Intermediate Amine (1.0 eq) was added and the reaction mixture was heatat 30-50° C. overnight. The crude reaction mixture was purified bypreparative HPLC using either [UV-Directed Low pH prep method] or[UV-Directed High pH prep method]. The fractions containing product werecombined and concentrated in vacuo to afford the title compound. Whereatropisomers were observed multiple retention times are quoted.

TABLE 13 Ex- Int. am- Acid/ RT ple Structure Amine NMR Data m/z (min)LCMS IUPAC Name 1-136

111/128 1H NMR (500 MHz, DMSO- d6) δ 7.71-7.65 (m, 1H), 7.61-7.45 (m,3H), 7.22 (t, J = 8.9 Hz, 1H), 7.17-7.10 (m, 1H), 7.10-7.02 (m, 1H),6.95- 6.83 (m, 1H), 5.08-4.70 (m, 1H), 4.64-4.38 (m, 1H), 4.21-3.92 (m,1H), 3.91- 3.68 (m, 3H), 3.67-3.37 (m, 5H), 2.94 (s, 1H), 2.86-2.70 (m,2H), 2.30-2.21 (m, 3H), 2.19-2.04 (m, 6H), 1.96- 1.79 (m, 2H), 1.77-1.60(m, 2H). 589 3.6, 3.10 Method 5 2-[4-({3-[(3S)- 4-(3,4-difluoro-phenyl)-3- (hydroxy- methyl)-5- oxopiperazine- 1-carbonyl]-2,4,6-trimethyl- phenyl}amino) piperidin-1- yl]benzonitrile 1-138

111/ Com- mercial 1H NMR (500 MHz, Chloroform-d) δ 8.47-8.37 (m, 1H),7.96 (dd, J = 59.3, 8.3 Hz, 1H), 7.75-7.70 (m, 1H), 7.58-7.53 (m, 1H),7.51- 7.43 (m, 1H), 7.17-7.10 (m, 1H), 7.03-6.96 (m, 2H), 6.90 (d, J =5.9 Hz, 1H), 4.66- 4.63 (m, 1H), 4.28-4.23 (m, 1H), 4.21-4.10 (m, 1H),4.10-4.03 (m, 1H), 4.02- 3.98 (m, 1H), 3.63-3.54 (m, 2H), 3.54-3.48 (m,1H), 3.12- 2.97 (m, 1H), 2.86-2.69 (m, 2H), 2.31-2.26 (m, 3H), 2.23-2.16(m, 6H), 2.14- 2.07 (m, 1H), 2.06-2.00 (m, 1H), 1.79-1.68 (m, 3H). 5234.63 Method 4 2-[4-({2,4,6- trimethyl-3-[3- oxo-4-(pyridin-2-yl)piperazine- 1-carbonyl] phenyl}amino) piperidin-1-yl] benzonitrile1-139

111/50 1H NMR (250 MHz, DMSO- d6) δ 7.69-7.48 (m, 2H), 7.28-6.90 (m,6H), 6.89- 6.68 (m, 4H), 4.74-4.27 (m, 1H), 4.13-3.93 (m, 1H), 3.76-3.24 (m, 8H), 2.90-2.75 (m, 2H), 2.26 (s, 3H), 2.17- 1.98 (m, 6H),1.98-1.84 (m, 2H), 1.79-1.54 (m, 3H). 552 4.55, 4.68, 4.79 Method 64-(3-{[1-(2- cyanophenyl) piperidin-4- yl]amino}- 2,4,6-trimethyl-benzoyl)- 1-phenyl- piperazine- 2-carboxamide 1-140

111/82 1H NMR (500 MHz, DMSO- d6) δ 8.55-8.51 (m, 1H), 7.67 (d, J = 7.7Hz, 1H), 7.59- 7.55 (m, 1H), 7.41-7.35 (m, 1H), 7.23-7.12 (m, 2H), 7.05(t, J = 7.5 Hz, 1H), 6.91- 6.82 (m, 1H), 4.97-4.16 (m, 4H), 3.79-3.66(m, 1H), 3.63- 3.39 (m, 4H), 3.29-2.70 (m, 7H), 2.26-2.22 (m, 3H),2.19-1.99 (m, 5H), 1.96- 1.77 (m, 3H), 1.75-1.58 (m, 2H) 540 2.09, 2.14,2.18, 2.24 Method 5 2-[4-({3-[(3S)- 3-(hydroxy- methyl)- 4-(pyridazin-3-yl)piperazine- 1-carbonyl]- 2,4,6- trimethyl- phenyl}amino)piperidin-1-yl] benzonitrile 1-142

100/50 1H NMR (500 MHz, Chloroform-d) δ 7.34-7.28 (m, 2H), 7.28-7.24 (m,2H), 7.23-7.16 (m, 1H), 7.03- 6.82 (m, 5H), 6.55 (s, 1H), 6.40 (s, 1H),5.64-5.48 (m, 1H), 4.76-4.65 (m, 0.5H), 4.33-4.29 (m, 0.5H), 4.25- 4.06(m, 0.5H), 3.97-3.73 (m, 2H), 3.68-3.61 (m, 0.5H), 3.60-3.24 (m, 5H),3.11-2.91 (m, 1H), 2.85- 2.66 (m, 2H), 2.26 (s, 3H), 2.22-1.90 (m, 9H),1.76- 1.61 (m, 2H). 570 4.64, 4.76, 4.87 Method 6 4-(3-{[1-(2- cyano-4-fluorophenyl) piperidin-4- yl]amino}- 2,4,6- trimethyl- benzoyl)-1-phenyl- piperazine- 2-carboxamide 1-143

100/ Commercial 1H NMR (500 MHz, Chloroform-d) δ 8.48-8.36 (m, 1H), 7.95(d, 1H), 7.76- 7.69 (m, 1H), 7.28-7.26 (m, 0H), 7.26-7.25 (m, 1H), 7.23-7.09 (m, 2H), 7.01-6.95 (m, 1H), 6.89 (d, J = 4.0 Hz, 1H), 4.64 (d, J =3.9 Hz, 1H), 4.28-4.23 (m, 1H), 4.18- 4.10 (m, 1H), 4.09-4.03 (m, 1H),4.00 (d, J = 4.4 Hz, 1H), 3.53-3.40 (m, 3H), 3.05- 2.94 (m, 1H),2.82-2.67 (m, 2H), 2.28 (d, J = 3.7 Hz, 3H), 2.26-2.13 (m, 7H), 2.12-1.97 (m, 3H), 1.77-1.62 (m, 2H). 560 4.73 Method 6 5-fluoro-2-[4-({2,4,6- trimethyl-3-[3- oxo-4-(pyridin- 2-yl)piperazine- 1-carbonyl]phenyl}amino) piperidin-1-yl] benzonitrile 1-144

100/86 1H NMR (500 MHz, Chloroform-d) δ 7.26-7.24 (m, 1H), 7.22-7.16 (m,1H), 7.04-6.95 (m, 3H), 6.93- 6.83 (m, 3H), 6.49-6.26 (m, 1H), 5.51-5.31(m, 1H), 4.48- 4.00 (m, 2H), 3.85-3.52 (m, 3H), 3.46 (s, 2H), 3.40- 3.26(m, 2H), 3.16-2.87 (m, 2H), 2.84-2.67 (m, 2H), 2.26 (s, 3H), 2.21-2.12(m, 6H), 2.11-1.95 (m, 2H), 1.77- 1.61 (m, 2H) 587 3.10, 3.14, 3.30,3.38 Method 5 4-(3-{[1-(2- cyano-4- fluorophenyl) piperidin-4-yl]amino}- 2,4,6-trimethyl- benzoyl)-1-(4- fluorophenyl) piperazine-2-carboxamide 1-145

70/119 1H NMR (500 MHz, Chloroform-d) δ 8.08-8.03 (m, 1H), 7.34-7.23 (m,3H), 7.01-6.88 (m, 4H), 6.65 (dd, J = 9.3, 3.0 Hz, 1H), 4.83- 4.02 (m,4H), 3.80-3.38 (m, 5H), 3.35-3.24 (m, 2H), 3.19- 3.03 (m, 2H), 2.89-2.57(m, 3H), 2.31-2.24 (m, 6H), 2.18 (d, J = 3.3 Hz, 3H), 2.02 (d, J = 9.8Hz, 2H), 1.50- 1.38 (m, 2H). 532 2.77, 2.91, 3.12, 3.19 Method 5[(2S)-4-(3- {[1-(5- fluoropyridin-2- yl)piperidin-4- yl]amino}-2,4,6-trimethyl- benzoyl)- 1-phenyl- piperazin- 2-yl]MeOH 1-149

101/122 1H NMR (500 MHz, DMSO- d6) 8.31 (d, J = 8.1 Hz, 1H), 8.08 (t, J= 4.9 Hz, 1H), 8.05 (d, J = 1.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H),7.56-7.49 (m, 1H), 6.88-6.81 (m, 1H), 6.76 (dd, J = 8.4, 3.4 Hz, 1H),6.62 (dd, J = 6.9, 5.0 Hz, 1H), 4.92- 4.20 (m, 3H), 4.08 (dd, J = 26.4,10.8 Hz, 1H), 3.69- 3.37 (m, 6H), 3.26-3.10 (m, 3H), 3.10-2.78 (m, 3H),2.20 (d, J = 5.2 Hz, 3H), 2.17- 2.09 (m, 3H), 1.97 (d, J = 16.6 Hz, 3H),1.91-1.72 (m, 2H), 1.52-1.31 (m, 2H). 516 2.79, 2.97, 3.02, 3.11 Method6 [(2S)-1- (pyridin-2- yl)-4-(2,4,6- trimethyl- 3-{[1-(pyrazin-2-yl)piperidin- 4-yl]amino} benzoyl) piperazin-2- yl]MeOH 1-150

101/20 1H NMR (500 MHz, DMSO- d6) δ 8.34-8.30 (m, 1H), 8.08-8.03 (m,1H), 7.80- 7.76 (m, 1H), 7.50 (dd, J = 47.5, 5.8 Hz, 1H), 7.24-7.11 (m,3H), 6.87-6.69 (m, 4H), 4.79-3.87 (m, 4H), 3.72- 3.39 (m, 5H), 3.27-2.96(m, 2H), 2.94-2.82 (m, 2H), 2.24- 2.17 (m, 3H), 2.09-1.98 (m, 6H),1.88-1.73 (m, 2H), 1.51-1.37 (m, 2H) 528 2.21, 2.36, 2.43, 2.56 Method 5(2S)-1-phenyl- 4-(2,4,6- trimethyl-3- {[1-(pyrazin- 2-yl) piperidin-4-yl]amino} benzoyl) piperazine- 2-carboxamide 1-152

101/73 1H NMR (500 MHz, DMSO- d6) δ 8.32 (s, 1H), 8.08-8.03 (m, 1H),7.80-7.75 (m, 1H), 7.50 (dd, J = 47.4, 5.9 Hz, 1H), 7.24-7.12 (m, 3H),6.86- 6.69 (m, 4H), 4.79-4.27 (m, 3H), 4.16-3.90 (m, 1H), 3.75-3.38 (m,5H), 3.28- 2.81 (m, 4H), 2.25-2.17 (m, 3H), 2.10-1.96 (m, 6H), 1.88-1.73 (m, 2H), 1.53-1.35 (m, 2H) 528 2.22, 2.36, 2.44, 2.56 Method 5(2R)-1-phenyl- 4-(2,4,6- trimethyl-3-{[1- (pyrazin-2- yl)piperidin-4-yl]amino} benzoyl) piperazine- 2-carboxamide 1-153

132/119 1H NMR (250 MHz, DMSO- d6) δ 7.58-7.36 (m, 2H), 7.30-7.07 (m,3H), 6.91 (d, J = 7.2 Hz, 2H), 6.84-6.67 (m, 1H), 4.73-3.98 (m, 2H),3.95- 3.19 (m, 12H), 2.46 (s, 3H), 2.36-2.01 (m, 6H), 2.00- 1.55 (m,4H). 557 4.52 Method 4 3-fluoro-2-[4- ({5-[(3S)-3- (hydroxy- methyl)-4-phenyl- piperazine-1- carbonyl]- 2,4,6-trimethyl- pyridin- 3-yl}amino)piperidin-1-yl] benzonitrile 1-154

134/119 1H NMR (250 MHz, DMSO- d6) δ 7.56 (dd, J = 8.3, 2.9 Hz, 1H),7.49-7.34 (m, 1H), 7.30- 7.11 (m, 3H), 6.92 (d, J = 7.0 Hz, 2H),6.84-6.67 (m, 1H), 4.70-3.99 (m, 2H), 3.97- 3.29 (m, 10H), 2.95-2.68 (m,3H), 2.46 (s, 3H), 2.38- 2.03 (m, 6H), 2.02-1.57 (m, 4H). 557 4.47Method 4 5-fluoro-2-[4- ({5-[(3S)-3- (hydroxy- methyl)- 4-phenyl-piperazine- 1-carbonyl]- 2,4,6-trimethyl- pyridin- 3-yl}amino)piperidin-1-yl] benzonitrile 1-155

136/119 1H NMR (250 MHz, DMSO- d6) δ 8.14-8.04 (m, 1H), 7.56- 7.41 (m,1H), 7.29-7.13 (m, 2H), 6.98-6.85 (m, 2H), 6.83- 6.70 (m, 2H), 6.64-6.50(m, 1H), 4.58-4.41 (m, 1H), 4.39- 4.00 (m, 3H), 3.92-3.30 (m, 7H),3.28-2.76 (m, 4H), 2.46- 2.42 (m, 3H), 2.34-2.03 (m, 6H), 1.90-1.76 (m,2H), 1.59- 1.38 (m, 2H). 515 4.02 Method 4 [(2S)-1-phenyl- 4-(2,4,6-trimethyl-5- {[1-(pyridin-2- yl)piperidin-4- yl]amino} pyridine-3-carbonyl) piperazin- 2-yl]MeOH 1-156

141/122 1H NMR (500 MHz, DMSO- d6) δ 8.13-8.04 (m, 2H), 7.57-7.44 (m,2H), 6.90- 6.73 (m, 3H), 6.67-6.53 (m, 2H), 4.90-4.35 (m, 2H), 4.33-4.01 (m, 4H), 3.65-3.37 (m, 3H), 3.28-3.10 (m, 3H), 3.10-2.91 (m, 2H),2.85- 2.70 (m, 2H), 2.20 (d, J = 5.2 Hz, 3H), 2.17-2.09 (m, 3H), 1.97(d, J = 16.6 Hz, 3H), 1.88- 1.70 (m, 2H), 1.40 (dq, J = 25.2, 12.1 Hz,2H). 515 1.02, 1.15, 1.18, 1.24 Method 5 [(2S)-1- (pyridin-2-yl)-4-(2,4,6- trimethyl- 3-{[1-(pyridin- 2-yl)piperidin- 4-yl]amino}benzoyl) piperazin-2- yl]MeOH 1-157

141/82 1H NMR (500 MHz, DMSO- d6) δ 8.53 (ddd, J = 7.1, 4.4, 1.0 Hz,1H), 8.13-8.05 (m, 1H), 7.53-7.45 (m, 1H), 7.37 (ddd, J = 9.4, 6.1, 4.5Hz, 1H), 7.28-7.13 (m, 1H), 6.88- 6.77 (m, 2H), 6.64-6.54 (m, 1H), 4.81(d, J = 88.6 Hz, 1H), 4.64-4.42 (m, 1H), 4.24 (dt, J = 19.8, 15.0 Hz,4H), 3.69- 3.52 (m, 2H), 3.51-3.37 (m, 2H), 3.26-2.91 (m, 4H), 2.79 (q,J = 11.6, 10.9 Hz, 2H), 2.21 (s, 3H), 2.17-2.06 (m, 3H), 1.97 (d, J =19.0 Hz, 3H), 1.78 (d, J = 11.6 Hz, 2H), 1.43 (q, J = 12.0 Hz, 2H). 5161.04, 1.13, 1.19, 1.23 Method 5 [(2S)-1- (pyridazin-3- yl)-4-(2,4,6-trimethyl-3-{[1- (pyridin-2- yl)piperidin-4- yl]amino} benzoyl)piperazin-2- yl]MeOH 1-158

102/119 1H NMR (500 MHz, DMSO- d6) δ 8.50 (ddd, J = 4.2, 2.8, 1.2 Hz,1H), 7.34 (ddd, J = 9.3, 4.3, 3.1 Hz, 1H), 7.28- 7.23 (m, 1H), 7.22-7.16(m, 2H), 6.92-6.81 (m, 3H), 6.74 (q, J = 7.1 Hz, 1H), 4.86- 4.03 (m,4H), 3.89-3.63 (m, 1H), 3.63-3.52 (m, 1H), 3.51- 3.33 (m, 3H), 3.29-3.17(m, 2H), 3.16-2.98 (m, 2H), 2.96-2.79 (m, 3H), 2.21 (d, J = 8.2 Hz, 3H),2.17-2.06 (m, 3H), 2.05-1.97 (m, 3H), 1.91- 1.73 (m, 2H), 1.53-1.33 (m,2H). 515 1.72 1.94, 1.97, 2.07 Method 5 [(2S)-1-phenyl- 4-(2,4,6-trimethyl-3-{[1- (pyridazin-3- yl)piperidin-4- yl]amino} benzoyl)piperazin-2- yl]MeOH 1-159

102/122 1H NMR (500 MHz, Chloroform-d) δ 8.62-8.54 (m, 1H), 8.20-8.08(m, 1H), 7.61-7.44 (m, 1H), 7.24- 7.15 (m, 1H), 7.00-6.85 (m, 2H),6.75-6.63 (m, 2H), 4.86- 4.62 (m, 1H), 4.52-4.16 (m, 3H), 3.99-3.75 (m,3H), 3.75-3.35 (m, 4H), 3.35- 3.11 (m, 3H), 3.05-2.86 (m, 2H), 2.34-2.20(m, 6H), 2.17- 2.10 (m, 3H), 2.10-1.96 (m, 2H), 1.54-1.39 (m, 2H) 5161.00, 1.12, 1.16, 1.22 Method 5 [(2S)-1- (pyridin-2-yl)-4-(2,4,6-trimethyl- 3-{[1- (pyridazin-3- yl)piperidin-4- yl]amino}benzoyl) piperazin-2- yl]MeOH 1-160

102/82 1H NMR (500 MHz, DMSO- d6) δ 8.49 (d, J = 4.4 Hz, 1H), 8.13-8.03(m, 1H), 7.58- 7.48 (m, 1H), 7.34 (dd, J = 9.3, 4.4 Hz, 1H), 7.28-7.21(m, 1H), 6.89-6.81 (m, 1H), 6.81-6.74 (m, 1H), 6.65- 6.58 (m, 1H),5.04-4.52 (m, 2H), 4.45-4.20 (m, 3H), 4.18- 3.95 (m, 2H), 3.30-2.79 (m,8H), 2.20 (d, J = 5.0 Hz, 3H), 2.18-2.08 (m, 3H), 2.02- 1.93 (m, 3H),1.91-1.71 (m, 2H), 1.55-1.33 (m, 2H).). 517 1.45 Method 4 [(2S)-1-(pyridazin-3- yl)-4-(2,4,6- trimethyl-3-{[1- (pyridazin-3-yl)piperidin-4- yl]amino} benzoyl) piperazin-2- yl]MeOH 1-161

102/124 1H NMR (500 MHz, Chloroform-d) δ 8.66-8.48 (m, 1H), 8.00 (dd, J= 6.1, 3.0 Hz, 1H), 7.34-7.27 (m, 1H), 7.20 (dd, J = 9.3, 4.5 Hz, 1H),6.99-6.78 (m, 2H), 6.64 (td, J = 10.3, 9.3, 3.0 Hz, 1H), 4.85-4.50 (m,1H), 4.48-4.21 (m, 3H), 3.91-3.75 (m, 2H), 3.65-3.30 (m, 3H), 3.28- 3.03(m, 3H), 3.03-2.84 (m, 2H), 2.30-2.21 (m, 7H), 2.12- 2.09 (m, 3H),2.09-1.99 (m, 3H), 1.50-1.38 (m, 2H). 534 1.58, 1.80, 1.83, 1.94 Method5 [(2S)-1-(5- fluoropyridin-2- yl)-4-(2,4,6- trimethyl-3-{[1-(pyridazin-3- yl)piperidin-4- yl]amino} benzoyl) piperazin-2- yl]MeOH1-162

102/86 1H NMR (500 MHz, Chloroform-d) δ 8.55 (t, J = 4.8 Hz, 1H),7.21-7.15 (m, 1H), 7.03-6.96 (m, 2H), 6.93- 6.83 (m, 4H), 6.53-6.32 (m,1H), 5.64-5.44 (m, 1H), 4.50-3.97 (m, 4H), 3.85- 3.09 (m, 6H), 3.02-2.84(m, 2H), 2.24 (s, 3H), 2.19-2.12 (m, 6H), 2.12-1.93 (m, 3H), 1.51-1.36(m, 2H) 546 1.62, 1.81, 1.89, 2.00 Method 5 1-(4- fluorophenyl)-4-(2,4,6-trimethyl- 3-{[1- (pyridazin-3- yl)piperidin-4- yl]amino}benzoyl) piperazine-2- carboxamide 1-163

102/90 1H NMR (500 MHz, DMSO- d6) δ 8.53-8.49 (m, 1H), 7.73- 7.67 (m,1H), 7.65-7.55 (m, 1H), 7.37-7.31 (m, 1H), 7.25 (q, J = 9.0, 8.2 Hz,2H), 7.19-7.07 (m, 1H), 6.90- 6.83 (m, 1H), 4.63 (d, J = 113.9 Hz, 1H),4.43-4.20 (m, 3H), 4.02-3.37 (m, 4H), 3.29- 3.13 (m, 3H), 3.13-2.96 (m,2H), 2.96-2.80 (m, 2H), 2.22 (d, J = 5.5 Hz, 3H), 2.17- 2.09 (m, 3H),2.09-2.04 (m, 4H), 1.81 (s, 2H), 1.54- 1.35 (m, 2H). 540 2.77, 2.90,2.94, 3.07 Method 6 2-[(2S)-2- (hydroxy- methyl)- 4-(2,4,6-trimethyl-3-{[1- (pyridazin-3- yl)piperidin-4- yl]amino} benzoyl)piperazin-1- yl]benzonitrile 1-165

138/119 1H NMR (500 MHz, DMSO- d6) δ 8.23-8.14 (m, 1H), 7.81- 7.73 (m,1H), 7.27-7.13 (m, 2H), 7.01-6.93 (m, 1H), 6.93- 6.86 (m, 2H), 6.80-6.66(m, 1H), 4.80 (s, 1H), 4.65-4.23 (m, 1H), 4.20-3.79 (m, 2H), 3.79-3.41(m, 5H), 3.26- 2.88 (m, 4H), 2.88-2.67 (m, 2H), 2.47-2.38 (m, 3H), 2.31-2.02 (m, 6H), 1.95-1.75 (m, 2H), 1.75-1.51 (m, 2H). 550 2.22, 2.30,2.32, 2.36 Method 5 [(2S)-4-(5- {[1-(3- chloropyridin-2- yl)piperidin-4-yl]amino}- 2,4,6- trimethyl- pyridine- 3-carbonyl)-1- phenyl- piperazin-2-yl]MeOH

Example 155: AlphaLISA Ultra pS6K1 assay

Assay Protocol:

-   -   1. Seed MCF-7 cells in Corning 3701 plate and incubate for 20˜24        hour. 12,000˜16,000 cells will be seeded in 36 μL medium per        well.    -   2. Change the culture medium with fresh medium and incubate for        another 2 hours.    -   3. Add 12 μL (4×) compounds into the cell plate by HAMILTON.        Final DMSO concentration is 0.5%. Incubate for 2 hours.    -   4. Aspirate 38 μL by HAMILTON, 10 μL rest per well.    -   5. Add 10 μL 2× lysis buffer using HAMILTON; total volume in        wells is 20 μL. Allow cells to shake for 30 min. Cover plate by        plastic foil and store plate at −80° C. up to analysis.    -   6. Thaw cell lysate at RT and transfer 10 ul lysate to assay        plate (Optiplate-384).    -   7. Add 5 ul acceptor beads into assay plate and incubation for 2        hours    -   8. Add 5 ul donor beads and incubation for 2 hours    -   9. Count the plate by EnSpire Multimode Plate Reader

TABLE 14 Key Reagents/Supplies Reagents/materials Vendor Cat. No. Lot.No. MCF-7 ATCC HTB-22 5105360 DMEM Invitrogen 12430-054 1677193 FBSInvitrogen 10099-141 1660516 0.25% Trypsin-EDTA Invitrogen 25200-0721638603 384 well plate, tissue Corning CLS3701 29214010 culture treatedCorning 384 well storage plates Corning CLS3656 29514036 Torin1 SelleckS2827 01 Rapamycin SELLECK S1039 08 OptiPlate-384, White OpaquePerkinElmer 6007299 8210-14501 384-well MicroPlate AlphaLISA SureFireUltra PerkinElmer ALSU-PP70- U0381 p-p70 S6 Kinase (Thr389) A10K AssayKit

Example 156: AlphaLISA Ultra pAKT Assay

Assay Protocol:

-   -   1. MCF-7 cells in Corning 3701 plate and incubate for 20-24        hour. 16,000-20,000 cells will be seeded in 36 μL medium per        well.    -   2. Change the culture medium with fresh medium and incubate for        another 2 hours.    -   3. Add 12 μL (4×) compounds into the cell plate by HAMILTON.        Final DMSO concentration is 0.5%. Incubate for 2 hours.    -   4. Aspirate 38 j L by HAMILTON, 10 μL rest per well.    -   5. Add 10 μL 2× lysis buffer using HAMILTON; total volume in        wells is 20 μL. Allow cells to shake for 30 min. Cover plate by        plastic foil and store plate at −80° C. up to analysis.    -   6. Thaw cell lysate at RT and transfer 10 ul lysate to assay        plate (Optiplate-384).    -   7. Add 5 ul acceptor beads into assay plate and incubation for 2        hours    -   8. Add 5 ul donor beads and incubation for 2 hours    -   9. Count the plate by EnSpire Multimode Plate Reader

TABLE 15 Key Reagents/Supplies Reagents/materials Vendor Cat. No. Lot.No. MCF-7 ATCC HTB-22 5105360 DMEM Invitrogen 12430-054 1677193 FBSInvitrogen 10099-141 1660516 0.25% Trypsin-EDTA Invitrogen 25200-0721638603 384 well plate, tissue culture Corning CLS3701 29214010 treatedCorning 384 well storage plates Corning CLS3656 29514036 Torin1 SelleckS2827 01 Rapamycin SELLECK S1039 08 OptiPlate-384, White OpaquePerkinElmer 6007299 8210-14501 384-well MicroPlate AlphaLISA SureFireUltra PerkinElmer ALSU-PAKT- U0329 p-Akt 1/2/3 (Ser473) B10K Assay Kits

Example 157: Radioactive Glucose Uptake in MCF-7 Cells

Assay Protocol

-   1. Seed approximately 12,000 MCF-7 cells cultured without insulin    per well in 96-well plates (BIOCOAT, #356690) and let the cells sit    in hood for 30 min. (Cell culture medium: DMEM+10% FBS).-   2. Put the cell culture plates in TC incubator (5% CO₂, 37° C.) and    incubate overnight.-   3. Take out the cell plates and wash with prewarmed KRH buffer (37°    C.) three times using BioTek plate washer. (KRH buffer preparation:    136 mM NaCl, 4.7 mM KCl, 1.25 mM MgCl₂, 1.2 mM CaCl₂), 20 mM HEPES,    0.1 mg/ml sodium pyruvate, 0.1% BSA, pH 7.4).-   4. Compound preparation and treatment:    -   a) Add 12 ul compound stock in 100% DMSO to the first column of        Echo LDV plate    -   b) Serially dilute the compound solution in 100% DMSO (4 uL+8 uL        DMSO) using Bravo for 9 doses    -   c) Dispense 350 nL compounds using Echo to the working plate.    -   d) i) Without compound preincubation condition, dispense 116 uL        KRH buffer containing tritiated 2-deoxy-D-glucose (3H-2DG) and        2-deoxy-D-glucose (2DG) to the working plate and mix.    -   ii. With compound preincubation condition, dispense 110 uL KRH        buffer only to the working plates and mix    -   e) Keep the compound working plate at 37° C. incubator until use-   5. Discard the KRH buffer (cells were kept in KRH buffer for 10-15    min before 2-DG addition) and transfer 100 uL compound working    solution out to the cell culture plate using Bravo. Incubate for 20    mins at 37° C. (2DG final at 0.2 mM, 3H-2DG at 10 uCi/mL).-   6. Add prewarmed 50 uL KRH buffer (37° C.) containing 60 mM cold 2DG    to the wells to stop the 2DG uptake using Multidrop combi-   7. Wash the cells with prewarmed PBS three times using BioTek plate    washer-   8. Add 50 uL lysis buffer (0.1 M NaOH) into the assay plate to lyse    the cells using Bravo and shake at 800 rpm for 30 min.-   9. Mix and transfer 20 uL lysate to a new white plate (Corning,    #3610) and add 200 uL MicroScint-20 using Bravo-   10. Shake the plate at 1000 rpm for 30 min and count in a MicroBeta    plate reader.

Example 158: ATP/Rotenone Assay

Assay Protocol

Day 1: Plate cells in Corning 96-Well Clear Bottom Black PolystyreneMicroplates (corning 3340) in Glucose-free DMEM+10% dFBS

-   -   80 uL/well    -   25,000 cells/well for 293T    -   10,000 cells/well for MCF7

Day 2:

Glucose DR to Establish Glucose EC50

-   1. 1 h pre-treat with 10 uM Rotenone    -   add 10 uL if 9× (90 uM) rotenone to each well (freshly made 10        mM stock diluted 1:111× in glucose-free DMEM.-   2. Stimulate with glucose for 15 min    -   Make glucose DR at 10× concentration in glucose-free DMEM    -   Add 10 uL per well and incubate at 37° C. for 15 min-   3. Reconstitute and Measure    -   Remove plate, immediately add 100 uL of reconstituted        Celltiter-Glo reagent (Promega; G7570) per well    -   Shake plate covered for 10 min at room temperature    -   Let plate sit for 2-5 min, read luminescence    -   Calculate EC50 for glucose (usually ˜1 mM for 293T cells and        ˜0.25 mM for MCF-7 cells).        Determine Compound IC50s-   1. 1 h pre-treat Rotenone/compound solution    -   Make 9× (90 uM) rotenone: 10 mM stock of Rotenone fresh—dilute        1:111× in Glucose-free DMEM).    -   Make compound dilution series in DMSO then dilute 1:111 in 90 uM        rotenone in glucose-free media    -   Add 10 uL of 9× rotenone/compound solutions per well-   2. Stimulate with glucose for 15 min    -   Make glucose DR at 10× concentration in glucose-free DMEM    -   Add 10 uL per well and incubate at 37° C. for 15 min        3. Reconstitute and Measure    -   Remove plate, immediately add 100 uL of reconstituted        Celltiter-Glo reagent (Promega; G7570) per well    -   Shake plate covered for 10 min at room temperature    -   Let plate sit for 2-5 min, read luminescence    -   Calculate IC50 for compounds

Table 16 shows the inhibitory activity (IC₅₀) of selected compounds ofthis invention in the pS6K1, pAKT, and glucose uptake assays. Thecompound numbers correspond to the compound numbers in Table 1.Compounds having an activity designated as “A” provided inhibitoryactivity (IC₅₀) of 0.01-1 μM; compounds designated as “B” providedinhibitory activity (IC₅₀) of 1-3 μM; compounds designated as “C”provided inhibitory activity (IC₅₀) of 3-5 μM; compounds designated as“D” provided inhibitory activity (IC₅₀) of 5-10 μM and compoundsdesignated as “E” provided inhibitory activity (IC₅₀) of >10 μM. “NA”stands for “not assayed.”

TABLE 16 Assay Data for Exemplary Compounds pS6K1 pAKT Glucose uptakeCompound in MCF7: in MCF7: in MCF7: Number IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM)I-1  A E A I-2  A E A I-3  A E A I-4  B E E I-5  B E NA I-6  E E E I-7 B E NA I-8  E E NA I-9  B E NA I-10  B E NA I-11  C E NA I-12  E E EI-13  C E NA I-14  A E A I-15  A E A I-16  A E NA I-17  B E NA I-18  B ENA I-19  B E NA I-20  B E NA I-21  C E NA I-22  C E C I-23  B E NA I-24 A E A I-25  A E A I-26  A E A I-27  B E NA I-28  B E NA I-29  A E NAI-30  A E NA I-31  A E NA I-32  B E NA I-33  D E NA I-34  B E NA I-35  CE NA I-36  D E NA I-37  B E NA I-38  C E NA I-39  E E NA I-40  A E NAI-41  B E NA I-42  A E NA I-43  A E A I-44  A E A I-45  A E A I-46  B ENA I-47  B E NA I-48  A E A I-49  A E A I-50  B E NA I-51  B E NA I-52 E E NA I-53  A E NA I-54  B E NA I-55  B E NA I-56  B E NA I-57  B E NAI-58  A E NA I-59  C E NA I-60  B E A I-61  A E A I-62  A E NA I-63  A ENA I-64  A E NA I-65  A E NA I-66  A E NA I-67  A E NA I-68  A E NAI-69  A E NA I-70  C E NA I-71  A E NA I-72  C E NA I-73  C E NA I-74  AE NA I-75  A E A I-76  A E NA I-77  A E NA I-78  E E NA I-79  A E AI-80  B E NA I-81  E E NA I-82  C E NA I-83  A E NA I-84  B E NA I-85  AE NA I-86  E E NA I-87  B E NA I-88  A E A I-89  A E NA I-90  C E NAI-91  D E B I-92  B E NA I-93  B E NA I-94  B E NA I-95  E E NA I-96  CE NA I-97  E E NA I-98  D E NA I-99  B E NA I-100 A E A I-101 B E NAI-102 A E A I-103 B E NA I-104 A E NA I-105 B E NA I-106 A E A I-107 C ENA I-108 B E NA I-109 C E NA I-110 A E NA I-111 A E A I-112 B E NA I-113C E NA I-114 E E NA I-115 B E NA I-116 B E NA I-117 A E NA I-118 B E NAI-119 E E NA I-120 A E NA I-121 A E A I-122 A E NA I-123 B E NA I-124 AE NA I-125 E E NA I-126 A E NA I-127 C E NA I-128 A E A I-129 B E NAI-130 C E C I-131 E E NA I-132 B E NA I-133 B E NA I-134 B E NA I-135 AE NA I-136 A E NA I-137 A E NA I-138 A E A I-139 A E NA I-140 A E NAI-141 A E A I-142 A E NA I-143 A E NA I-144 A E NA I-145 A E NA I-146 AA NA I-147 A E NA I-148 A E NA I-149 A E NA I-150 A E NA I-151 A E NAI-152 E E NA I-153 A E NA I-154 B E NA I-155 B E NA I-156 A E NA I-157 AE NA I-158 A E NA I-159 A E A I-160 B E NA I-161 A E NA I-162 A E NAI-163 A E NA I-164 A E NA I-165 A E NA I-166 B E E I-167 B E NA I-168 AE NA I-169 B E NA I-170 A E NA I-171 A E A I-172 C E NA I-173 B E NAI-174 A E NA I-175 A E NA I-176 A E A I-177 B E NA I-178 A E NA I-179 AE NA I-180 A E NA I-181 A E NA I-182 A E A I-183 A E NA I-184 A E NAI-185 A E NA I-186 A E NA I-187 E E NA I-188 B E NA I-189 A E NA I-190 AE NA I-191 A E A I-192 A E A I-193 B E NA I-194 A E A I-195 B E C

We claim:
 1. A method for treating a mTORC-mediated cellularproliferative disorder in a patient in need thereof, comprisingadministering to said patient a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: A¹ is N or CH;A² is N(Ring A); A³ is C(R′) or N; A⁴ is CH or N; R′ is H, C 1-6aliphatic, or halogen; each R is independently hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, a 3-8 membered saturatedor partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each of m, n,p, q, and x is independently 0, 1, or 2; each of y and z isindependently 0, 1, 2, 3 or 4; each of R¹ and R² is independently R, or:two R¹ groups are optionally taken together to form ═O; two R² groupsare optionally taken together to form ═O; two R¹ groups are optionallytaken together to form a covalent bond or a bivalent C₁₋₄ alkylenechain; or two R² groups are optionally taken together to form a covalentbond or a bivalent C₁₋₄ alkylene chain; an R¹ group and Ring A areoptionally taken together with their intervening atoms to form a 5-8membered fused ring having 0-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur; or an R² group and Ring B are optionallytaken together with their intervening atoms to form a 5-8 membered fusedring having 0-2 heteroatoms independently selected from nitrogen, oxygenor sulfur; each of R³ is independently R, halogen, —OR, —CN, or two R³groups are optionally taken together with their intervening atoms toform a 5-8 membered partially unsaturated or aryl fused ring having 0-2heteroatoms independently selected from nitrogen, oxygen, or sulfur; R⁴is hydrogen or an optionally substituted C₁₋₆ aliphatic group; Ring A isan optionally substituted ring selected from 6-membered aryl containing0-2 nitrogen atoms, 5-membered heteroaryl with 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur, or 8-10 memberedbicyclic aryl or heteroaryl with 1-4 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur; Ring B is an optionally substitutedring selected from 6-membered aryl containing 0-2 nitrogen atoms,5-membered heteroaryl with 1-4 heteroatoms independently selected fromnitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl or heteroarylwith 1-4 heteroatoms independently selected from nitrogen, oxygen orsulfur; and L¹ is a covalent bond or a C₁₋₃ bivalent straight orbranched saturated or unsaturated hydrocarbon chain wherein 1-2methylene units of the chain are independently and optionally replacedwith —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, or —S(O)₂—,or a pharmaceutical composition thereof.
 2. A method of treating cysticfibrosis in a patient in need thereof, comprising administration to saidpatient a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: A¹ is N or CH;A² is N(Ring A); A³ is C(R′) or N; A⁴ is CH or N; R′ is H, C 1-6aliphatic, or halogen; each R is independently hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, a 3-8 membered saturatedor partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each of m, n,p, q, and x is independently 0, 1, or 2; each of y and z isindependently 0, 1, 2, 3 or 4; each of R¹ and R² is independently R, or:two R¹ groups are optionally taken together to form ═O; two R² groupsare optionally taken together to form ═O; two R¹ groups are optionallytaken together to form a covalent bond or a bivalent C₁₋₄ alkylenechain; or two R² groups are optionally taken together to form a covalentbond or a bivalent C₁₋₄ alkylene chain; an R¹ group and Ring A areoptionally taken together with their intervening atoms to form a 5-8membered fused ring having 0-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur; or an R² group and Ring B are optionallytaken together with their intervening atoms to form a 5-8 membered fusedring having 0-2 heteroatoms independently selected from nitrogen, oxygenor sulfur; each of R³ is independently R, halogen, —OR, —CN, or two R³groups are optionally taken together with their intervening atoms toform a 5-8 membered partially unsaturated or aryl fused ring having 0-2heteroatoms independently selected from nitrogen, oxygen, or sulfur; R⁴is hydrogen or an optionally substituted C₁₋₆ aliphatic group; Ring A isan optionally substituted ring selected from 6-membered aryl containing0-2 nitrogen atoms, 5-membered heteroaryl with 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur, or 8-10 memberedbicyclic aryl or heteroaryl with 1-4 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur; Ring B is an optionally substitutedring selected from 6-membered aryl containing 0-2 nitrogen atoms,5-membered heteroaryl with 1-4 heteroatoms independently selected fromnitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl or heteroarylwith 1-4 heteroatoms independently selected from nitrogen, oxygen orsulfur; and L¹ is a covalent bond or a C₁₋₃ bivalent straight orbranched saturated or unsaturated hydrocarbon chain wherein 1-2methylene units of the chain are independently and optionally replacedwith —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, or —S(O)₂—,wherein said compound is an inhibitor of glucose transporters 1, 2, 3,4, and 5, or a pharmaceutical composition thereof.
 3. The methodaccording to claim 1 or claim 2, wherein A¹ is N.
 4. The methodaccording to claim 3, wherein m is 1 and n is
 1. 5. The method accordingto claim 3, wherein A³ is C(R′).
 6. The method according to claim 3,wherein A⁴ is CH.
 7. The method according to claim 3, wherein p is 1 andq is independently 0, 1, or
 2. 8. The method according to claim 3,wherein each of R¹ and R² is independently R, or: two R¹ groups areoptionally taken together to form ═O; two R² groups are optionally takentogether to form ═O; two R¹ groups are optionally taken together to forma covalent bond or a bivalent C₁₋₄ alkylene chain; or two R² groups areoptionally taken together to form a covalent bond or a bivalent C₁₋₄alkylene chain.
 9. The method according to claim 4, wherein R¹ is


10. The method according to claim 8, wherein R² is hydrogen or methyl.11. The method according to claim 3, wherein, each of R³ isindependently R, halogen, —OR, or —CN.
 12. The method according to claim3, wherein Ring A is


13. The method according to claim 3, wherein Ring B is an optionallysubstituted ring selected from 6-membered aryl containing 0-2 nitrogenatoms.
 14. The method according to claim 13, wherein Ring B is


15. The method according to claim 3, wherein L¹ is a covalent bond or aC₁₋₃ bivalent straight or branched saturated or unsaturated hydrocarbonchain wherein 1-2 methylene units of the chain are independently andoptionally replaced with —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—,—N(R)—, or —S(O)₂—.
 16. The method according to claim 3, wherein saidcompound is of Formula II:

or a pharmaceutically acceptable salt thereof, wherein each R^(∘) is amonovalent substituent independently selected from: halogen,—(CH₂)₀₋₂R^(•), -(haloR^(•)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•),—(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(•),—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•), —(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•), —(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃,-OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄ straight or branchedalkylene)C(O)OR^(•), or —SSR^(•), wherein each R^(•) is unsubstitutedor, where preceded by “halo” is substituted only with one or morehalogens, and is independently selected from C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.
 17. The method according to claim 3, wherein thecompound is selected from:

or pharmaceutically acceptable salt thereof.
 18. The method of claim 1,wherein the mTORC-mediated cellular proliferative disorder is a fibroticdisease selected from idiopathic pulmonary fibrosis (IPF), kidneyfibrosis, scleroderma, hypertrophic scarring, keloid disease, andcardiac fibrosis.